An immunologic portrait of cancer
© Ascierto et al; licensee BioMed Central Ltd. 2011
Received: 29 April 2011
Accepted: 29 August 2011
Published: 29 August 2011
The advent of high-throughput technology challenges the traditional histopathological classification of cancer, and proposes new taxonomies derived from global transcriptional patterns. Although most of these molecular re-classifications did not endure the test of time, they provided bulk of new information that can reframe our understanding of human cancer biology. Here, we focus on an immunologic interpretation of cancer that segregates oncogenic processes independent from their tissue derivation into at least two categories of which one bears the footprints of immune activation. Several observations describe a cancer phenotype where the expression of interferon stimulated genes and immune effector mechanisms reflect patterns commonly observed during the inflammatory response against pathogens, which leads to elimination of infected cells. As these signatures are observed in growing cancers, they are not sufficient to entirely clear the organism of neoplastic cells but they sustain, as in chronic infections, a self-perpetuating inflammatory process. Yet, several studies determined an association between this inflammatory status and a favorable natural history of the disease or a better responsiveness to cancer immune therapy. Moreover, these signatures overlap with those observed during immune-mediated cancer rejection and, more broadly, immune-mediated tissue-specific destruction in other immune pathologies. Thus, a discussion concerning this cancer phenotype is warranted as it remains unknown why it occurs in immune competent hosts. It also remains uncertain whether a genetically determined response of the host to its own cancer, the genetic makeup of the neoplastic process or a combination of both drives the inflammatory process. Here we reflect on commonalities and discrepancies among studies and on the genetic or somatic conditions that may cause this schism in cancer behavior.
It was about a decade ago when the first studies attempting to re-classify cancer according to global transcript analysis were published [1–3]. A countless number of publications followed attempting to reshape the landscape of cancer based on transcriptional or other high-throughput platforms for better diagnosis, prognosis and prediction of cancer behavior. As the galore of expectations triggered by these investigations is settling into a more realistic perspective, consistent observations are emerging from the bulk of information that sparkle novel insights on the biology of cancer. These observations describe a cancer phenotype characterized by immune effector mechanisms that are commonly observed during acute inflammation.
Under certain conditions, inflammation seems to promote carcinogenesis, whereas in other situations it seems to have anti-tumor effects. The intensity and nature of the inflammation could explain this apparent contradiction [4, 5]. In most cases, the inflammation associated with cancer is similar to that seen with chronic inflammation, characterized by the production of growth and angiogenic factors that stimulate tissue repair and growth. Macrophages are the primary source of secreted pro-inflammatory cytokines and tumor macrophage infiltration has been shown to be an independent predictor of poor prognosis in malignancies such as lymphoma, non small cell lung cancer and hepatocellular carcinoma [6–8]. Occasionally, however, it is observed a cancer inflammatory process, similar to acute inflammatory processes, characterized by the presence of innate and adaptive T cell responses which favors an immune effector mechanism capable of inducing spontaneous or treatment-induced cancer regression. In this process the presence of intrinsic immune signatures reminiscent of an anti-viral state is painting a new portrait of cancer . This portrait includes paradoxical relationships between the role of immunity in modulating cancer growth versus rejection [4, 10–13]. Furthermore, the canonical role played by the immune system in recognizing and clearing aberrant tissues broadens its functions to modulate tissue regeneration, angiogenesis and pro- or anti-apoptotic mechanisms, which in turn may affect directly or indirectly the natural history of cancer [14–16].
Immune signatures in melanoma
Prospective molecular profiling of melanoma metastases undergoing immunotherapy with the systemic administration of high dose interleukin (IL)-2 suggested that lesions likely to undergo complete regression were immunologically activated before therapy . Recently, in a pilot study of 19 patients vaccinated with a combination of four tumor antigens plus IL-12, Gajewski et al.  observed by global transcriptional analysis that tumors of patients who respond to therapy display a pre-existing inflamed status characterized by the expression of interferon stimulated genes (ISGs). Moreover, expression of T cell attracting chemokines such as CCL2/MCP-1, -3/MIP1α, -4/MIP1β, -5/RANTES and CXCL-9/Mig and -10/IP-10 was observed at the transcriptional and subsequent  protein level. These findings were associated with the histopathological demonstration of a brisk infiltrate of CD8+ T cells in the same tumors. The role of these chemokines in recruiting activated effector T cells was confirmed in vitro and in reconstituted xenografts. Interestingly, together with the effector component of the immune response, the inflamed tumor phenotype also displayed the presence of immune inhibitory mechanisms including the expression of indoleamine-2,3-dioexygenase, PD-L1 and T regulatory cells. These findings suggest that tumors of the inflamed phenotype do not discriminate among various components of the immune response as they can sustain immune effector and immune regulatory functions simultaneously; it is probably the overall balance between the two vectors that determines the ultimate fate of these cancers individual cancers. More recently, the same group identified a similar pattern predictive of favorable outcome in patients vaccinated with dendritic cell loaded with multiple tumor antigen-derived peptides . Similar findings were observed by GSK-Biologics in non small cell lung cancer and melanoma patients undergoing vaccination with MAGE-3 protein [29, 30]. An inflammatory phenotype was also found to be predictive of good outcome in patients with melanoma treated with IL-2 [21, 31] or anti-CTLA-4 mAb . Moschos et al  observed a higher density of dendritic cells and T cells in melanomas of patients who exhibited clinical response to adjuvant high dose IFN-α therapy; the same group identified a higher expression of phosphorylated STAT1 tyr701 (pSTAT1) and higher pSTAT1/pSTAT3tyr705 in cancer cells of patients with tumors displaying this type of infiltrate and this was associated with longer overall survival . Treatment with IFN-α further enhanced the levels of pSTAT1 while decreasing those of pSTAT3 and total STAT3 in tumor cells further altering the balance between the two transcription factors in favor of the pro-inflammatory and pro-apoptotic phenotype [35–37]. As a functional correlate, it was observed that increased pSTAT1/pSTAT3 ratios were associated with down-stream increase in expression of ISGs by tumor cells including tapasin 2, a protein whose expression is tightly regulated down-stream of pSTAT1 signaling through the master regulator of the acute inflammatory process IRF-1 . Similar variation in constitutive levels of pSTAT-1 could be observed in melanoma cells by Lesinski et al  who also observed that pSTAT1/pSTAT3 levels were inversely affected by IFN-α treatment; these enhanced ratios correlated with anti-proliferative effects of IFN-α.
Interestingly, others did not observe such a relationship between presence of tumor infiltrating lymphocytes and improved survival in patients with metastatic melanoma although the absence of tumor infiltrating lymphocytes predicted the development of lymph node metastases .
Immune signatures in other cancers
Immune cellular and molecular patters associated with outcome in cancer
T cell infiltrate
Response to ITx
Response to CTx
Skin/Head and Neck/Anal Squamous Cell Carcinoma
Suppression of tumor growth
T cells represent the dominant immune infiltrate in ovarian cancer and the presence of CD8-expressing T cells within the intra-epithelial compartment is a strong predictor of improved survival [40, 43, 70]. Although most ovarian cancers harbor T cells in the surrounding stroma, approximately 50% of them are infiltrated in the intra-epithelial compartment. Independent of response to chemotherapy, when this infiltrate is present, the five year survival is 35% compared to 4.5%. Several studies have confirmed these findings in various ethnic groups [71–77] providing indisputable evidence that T cell infiltration is strongly associated with an improved survival in ovarian cancer. As pointed out by Kandalaft and Coukos , it remains, however, unclear whether the T cell infiltrate bears a causative effect on the improved survival by effectively eliminating tumor cells or rather represents a sign of indolent tumor cell biology characterized by slower growth that enhances the chance for immune cells to infiltrate the tumor microenvironment. This hypothesis is challenged by the observation that tumors with a potentially higher proliferation index are in general those characterized by higher T cell infiltrate . This may be due to a higher mutational rate of these tumors that results in higher immunogenicity due to the expression of neo-antigens ; this phenomenon has been also hypothesized for BRCA1 in breast and colon cancers in which microsatellite instability induces more undifferentiated tumors and denser T cell infiltrates. Alternatively, tumor-reactive T cells may have dual function inhibiting tumor growth and at the same time inducing epigenetic changes in the tumor cells that leads to tumor escape. For instance, we have shown that C producing T cells can induce methylation of the neu promoter, resulting in neu antigen loss and tumor relapse . Recently, we observed an inverse correlation between HER-2/neu-specific immune responses and HER-2/neu expression in the tumors of patients with breast carcinoma. Such inverse correlation was associated with nuclear translocation of IFN-γ Ra in the tumor cells . However, despite the increased tumor differentiation and malignancy, the greater presence of T cell infiltrated is associated with overall favorable prognosis [81, 82].
Intra-epithelial T cell infiltrates in ovarian cancer have been associated with enhanced expression of IFN-α, IL-2 and HLA class I molecules [40, 83] suggesting that the T cell infiltrate is associated with activation of a Th1 type of immune responses. More recently, it was observed that ovarian and other cancers can be heavily infiltrated with IL-17-producing T cells and their presence is often accompanied by that of IFN-α/IL-2-expressing T cells . It was observed that IL17 and IFN-α synergistically stimulate the production of CXCL-9/Mig, -10/IP-10 and -11/ITAC chemokines in correlation with strong T cell infiltrate . These chemokines primarily attract activated T cells expressing their receptor CXCR3 . Other chemokines including CCL21/SLC/Exodus2 and CCL22/MDC were highly expressed in tumors with immune infiltrates, while an inverse correlation between presence of IL-17-expressing T cells and regulatory T cells was observed. Overall, the combined expression of IFN-γ and IL-17 expressing T cells was predictive of improved survival. As discussed later it was also observed that the presence of IL-17-expressing T cells was due to the secretion of IL-1β and IL-23 p19 by tumor infiltrating macrophages. This positive role of IL-23 p19 on survival of patients with ovarian cancer was also reported by an independent group which observed that high IL-12 p35 and IL-23 p19 transcriptional levels were associated with better outcome in ovarian cancer .
In 1998, Naito et al reported a correlation between infiltration of colon cancers by CD8 expressing T cells and improved survival . It was subsequently recognized that CD8+, CD45RO+, CD68+ T cells were mostly present in the cases with good prognoses . Recent investigations of the primary tumor microenvironment in colorectal cancer allowed the uncovering of four major intra-tumor immune profiles respectively characterized by: 1) a strong and coordinated cytotoxic Th1 immune phenotype expressing CD8+, CD45RO+ T cells, the transcription factor T-box protein 21 (T-bet), interferon regulatory factor (IRF)-1, interferon (IFN)-γ, granulysin and granzyme-B; 2) tumor angiogenesis (VEGF); 3) non-coordinated immune responses and, 4) a weak immune reactive phenotype [14, 45]. The first transcriptional phenotype corresponded to immunohistochemical evidence of CD8 T cell infiltration and was characterized by good prognostic significance when the T cells were present both in the center and in the invasive margins of the tumors. These signatures were associated with lack of expression of histological markers associated with metastatic behavior such as vascular emboli, lymphatic invasion and peri-neural invasion (collectively termed VELIPI). This re-classification was more reliable in predicting disease outcome than conventional TNM staging. It was later observed that the expression of the aforementioned Th1 type genes is tightly regulated probably by the expression of IFN-γ . Interestingly, recent independent studies observed a paradoxical association between the infiltration of colon cancer by T cells expressing the T regulatory cell marker FoxP3 [49, 52, 86, 87] or PD-1  and favorable prognosis in patients undergoing chemo- or chemo-immunotherapy. This observation is in line with the previously described association between a longer disease free survival and the presence of FoxP3 T regulatory cells in head and neck and ovarian cancer. As no transcriptional analysis was performed in these studies, it is unknown whether this represents a distinct cancer phenotype or rather that the expression of FoxP3 is also, though paradoxically, a component of the more broadly described immune phenotype. More recently Tosolini et al., by profiling colon cancer biopsies, described two clusters of genes associated with regulatory functions. Although the first cluster (IL-10/TGFβ) was not associated with a favorable outcome, the FoxP3 (second cluster) mRNA expression and the presence of high density FoxP3 positive cells were associated with better survival . The same observation was made in a recent study whereon patients with metastatic melanoma received high-dose interleukin-2 plus the gp100:209-217(210M) peptide vaccine. The vaccine plus interleukin-2 group, as compared with the interleukin-2 only group, experienced a significant improvement in overall clinical response and longer progression-free survival. It was also noted an increase in CD4+FOXP3+ T cells in patients who responded to therapy independent of the treatment received. It was hypothesized that the increased levels of T regulatory cells in patients who had a response to treatment represent a counter regulatory response after a strong anti-tumor immune reaction .
In addition, the evidence that regulatory T cells can lose FoxP3 , effector T cells can transiently express FoXP3 without acquisition of suppressive functions [91, 92] and FoxP3 acts as tumor suppressor gene and it is expressed on tumor cells [93–95] complicates the interpretation of the aforementioned studies in absence of functional and cell-specific analyses.
Furthermore, Denkert et al  observed that a robust pre-existing intra-tumor and stromal lymphocytic infiltration was a significant independent predictor of complete response to anthracycline/taxane neo-adjuvant chemotherapy. In particular, this study identified CXCL9/Mig to be strongly associated with intra-tumor lymphocytic infiltrate and better responsiveness in all cohorts of patients studied. Furthermore, statistical evaluation suggested that the response to chemotherapy was dependent on lymphocytic infiltrates and that CXCL9/Mig expression varied gradually among lesions as a continuous parameter. Conversely, elevated expression of IRF-2 (an inhibitor of IRF-1 transcriptional activity) and high IRF-2/IRF-1 ratios were observed to be associated with worse prognosis in esophageal cancer . Since IRF-1 is a central modulator of the expression of the CXCR3 ligand chemokines, this study reinforces the relevance of the IFN-γ/STAT-1/IRF-1 axis as a favorable prognostic factor in cancer.
Besides the preclinical evidence suggesting that anticancer immune responses contribute to the success of chemotherapy, Ladoire S. et al  observed that also the nature of tumour-infiltrating lymphocytes after neoadjuvant chemotherapy could be used as a predictive factor for survival of breast cancer patients. Studying a series of 111 consecutive HER2- and a series of 51 non-HER2-overexpressing breast cancer patients treated by neoadjuvant chemotherapy, it was observed that high CD8 and low FOXP3 cell infiltrates after chemotherapy were significantly associated with improved relapse free survival (p = 0.02) and OS (p = 0.002), and this predictive pair outperformed classical predictive factors in a multivariate analysis.
Interestingly, an older study observed an opposite pattern whereby lymphocytic infiltrate was associated with worse 5 year disease-free survival and with reduced estrogen receptor expression . However, in that case, no functional assessment of the immune infiltrate could be inferred through transcriptional signatures. Additionally, the down regulation of estrogen receptor genes in samples with lymphocytic infiltration could have driven the results, since the estrogen receptor negative tumors are insensitive to endocrine therapy. In fact, the hormonal treatment can dramatically improve the prognosis of the estrogen receptor positive tumors, thereby counterbalancing the negative effect of the absence of tumor infiltrating lymphocytes .
Wallace et al.  reported signatures related to activation of interferon stimulated genes (ISGs) in primary prostate cancer of patients of African American ancestry; these signatures, contrary to what observed by previous groups in other cancers, were associated with a worse prognosis in individuals of this ethnic background compared to European Americans. However, although a common theme related to enhanced interferon signaling was observed by both groups, the latter did not observe activation of the typical inflammatory genes described by the former centered on the IFN-γ/IRF-1 pathway rather signatures more typically related to signaling down-stream of type 1 IFNs such as IFN-α or -β and to the induction of angiogenesis. In fact, immunohistochemical analysis demonstrated that these signatures where associated with enhanced angiogenesis and, contrary to the colon study, infiltration of tumor associated macrophages rather than T cells; these observations are, therefore, opposite of those observed in colon cancer suggesting that these immune active prostate cancers have a VELIPI phenotype. Moreover, the same group observed a immune phenotype of basal-like breast cancer portraying a higher frequency of FoxP3-expressing T regulatory cells and characterized by poorer prognosis . It was also observed that upon separation of tumor epithelium from tumor stroma by micro-dissection, the immune signatures were predominantly expressed by the latter. These observations suggest that the cancer immune phenotype comes in different flavors which can be partly attributed to a mixed activation of pathways associated to type II or type I IFN signaling and possibly the latter displays a less clear prognostic value.
On the origin of immune signatures
Together with gene expression profiling, immunohistochemical (IHC) validation of gene expression data and tissue microarrays (TMAs) are useful tools to clarify the prognostic relevance of gene expression in discrete tumor tissues [100, 101]. However, IHC and TMAs techniques are limited by the subjectivity of scoring methods compared to transcriptional profile which give objective or quantitative information that can be normalized to standard reference samples.
Although gene expression analysis has proven accurate in the characterization of the tissue microenvironments supporting the relevance of ongoing immune responses, it cannot provide information about the source cell expressing immune effectors gene. Based on transcriptional evidence, it is generally assumed that signatures of immune activation identified by testing whole cancer tissue reflect activation of genes expressed by infiltrating immune cells. However, we recently compared immunologic signatures of primary pancreatic cancer tissues pancreatic cancer cell lines and observed activation of innate immunity including activation of ISGs in both . Moreover, primary xenografts displayed a similar dichotomy between an immune active and an inactive phenotype. Immunohistochemistry analysis of primary tumor lesions confirmed the expression of MxA, a typical ISGs. Thus, it is likely that the immune signatures expressed by cancer tissues are, at least in part, due to the activation of immune mechanisms intrinsic to the tumor cell biology. Indeed, others have observed signs of immune activation in cultured melanoma cell lines which displayed constitutive pSTATs activation . Similarly, Zeimet et al  in a study including 138 ovarian cancer samples observed high levels of IRF-1 expression in cancer cells; the high expression of IRF-1 by cancer cells was associated with enhanced presence of CD3+ T cell which only occasionally stained positively for IRF-1. In this case, however, it is difficult to predict whether IRF-1 expression was secondary to the secretion of IFN-γ by the T cells, which, in turn, are insensitive to autocrine activation due to down-regulation of the IFN-γ receptor . Thus, the best evidence that the immune signatures observed in the tumor microenvironment are, at least in part, driven by the intrinsic cancer cell biology resides in the constitutive activation of immune genes observed in resting cancer cells in vitro. It is interesting to note that the constitutive activation of cancer cells observed in vitro through the detection of the phosphorylation of STAT-1 is generally modest; yet it corresponds to a transcriptional profile fully associated with the coordinate expression of ISGs activated downstream of the STAT-1/IRF-1 axis. Moreover, it appears that this constitutive activation of pSTAT-1, though mild, predisposes cell lines to higher sensitivity to further stimulation with IFN-γ [38, 104].
Currently, no correlative study has been reported to test whether the signatures observed in immune activated tumors are also present in cell lines derived from the same tumors. It is important to note, however, that expression of various transcription factors associated with IFN signaling by cancer cells has been broadly described in various tumors  and it has been associated with better overall survival at least in melanoma . Moreover, it is believed that activation of such transcription factors such as members of the STAT family is at least in part mediated by activation of various oncoproteins involved in tyrosine kinase signaling [35, 37]. Thus, although it is not clear why TIL are present in some and not all tumors, it is becoming increasingly clear that some intrinsic characteristics of the tumor cells themselves may drive in part the presence of immune infiltrates. For instance, secretion of endothelial factors and chemokines by tumor cells has been deemed responsible for this phenotype in various cancer models [27, 105–107]. It is also possible that the borderline constitutive immune activation or anti-viral state of cancer cells in vivo perpetuate a positive feedback loop whereby the cancer cells not only invite immune cells to the tumor microenvironment but they are also more sensitive to pre-inflammatory factors secreted by immune cells. A recent commentary outlines different characteristics of the tumor cells that may explain paradoxical observations on tumor infiltrating cells of the immune system .
Prognostic significance of immune signatures
Constitutive production of immune stimulatory molecules and activation of immune mechanisms in cancer cells is likely to drive the homing of immune cell within the tumor microenvironment as recently demonstrated in experimental models [27, 109]. It is also possible that the constitutive immune activation of cancer cells makes them more sensitive to immune stimulatory mechanisms induced by TIL as suggested by the enhanced expression of pSTAT-1 in response to IFN-α stimulation . However, the activation of innate immune mechanisms may have broader implications than those predicted by direct immune interactions. IRF-1 and IRF-5 for instance are powerful pro-apoptotic transcriptional activators which directly inhibit the cyto-protective activity of other pro-survival factors such as NF-k B [110–112]. Moreover, IRF-1 inhibits VEGF expression thereby exhibits anti-angiogenic effects . Thus, the paradoxical observation that signatures of actively growing tumors are similar to signatures of immune-mediated tissue-specific destruction during acute rejection [9, 10] may be explained by a borderline situation in which immune activation is not sufficient to activate all the mechanisms required to clear the organism of cancer cells; however, these tumors are more susceptible to fluctuations of immune functions driven by environmental conditions such as sporadic viral infections or the pro-inflammatory effects of chemotherapy  or immune therapy  that can suddenly shift the balance toward partial or complete tumor elimination.
Constitutive expression and activation of STAT-3, a common oncogenic signaling pathway, has been clearly associated with cancer progression and poor prognosis . Moreover, Wang et al.  showed an inverse correlation between STAT-3 activation in tumor cells and expression of pro-inflammatory cytokines associated with adaptive and innate immune responses. Thus, it is possible that activation of the IFN-γ/STAT-1/IRF-1 pathways serves to counteract the constitutive activation of STAT-3 in some cancer cell lines in the context of metastatic melanoma . While experimental models support this hypothesis, very little is known about the association of various STAT proteins in cancer cells with immune infiltrates.
The mechanisms leading to immune activation of cancer cells and/or microenvironment
It could be argued that infiltration of the immune cells into the tumor site is a characteristic dictated by the genetic background of the host . Indeed polymorphisms in the expression of cytokine receptors, CXCR3 and CCR5 in particular, have been implicated in the ability of the host to mount effective immune responses in several pathological conditions including allograft rejection . Considering the central role that the ligands for these receptors play in immune-mediated tumor rejection, it is reasonable to speculate that genetic polymorphism may be in part responsible for the tumor infiltration of the immune cells and polymorphism of several genes could represent a multi factorial component of this phenomenon. This is just an example of the genetic variants that could affect the infiltration of tumors in some but not all patients. At the transcriptional level, expression of CXCR3 and CCR5 ligands is tightly controlled by the activation of the IFN-γ/STAT-1/IRF-1 axis; however, when the expression of the CXCL-9, CXCL-11 and CCL-5 is assessed in melanoma metastases, almost a perfect correlation is observed between them and their respective receptors CXCR3 and CCR5 expressed by tumor-infiltrating T cells and NK cells. It is possible that polymorphisms in the expression of these receptors may variably influence trafficking of the immune cells to tumors that express comparable levels of the relevant chemokine (Figure 2). Alternatively, it is possible that the presence of T cells may be dictated by factors other than the chemokines such as the expression of antigen and antigen presenting molecules that could induce the expansion and persistence of T cells reaching the tumor.
It is also possible that the genetics of the tumor may drive infiltration of different cells of the immune system to the tumor site [73, 78, 81, 82]. For instance, it was observed that ovarian cancers with p53 mutations are more frequently infiltrated with intraepithelial T cells . Although these findings could be interpreted as a higher likelihood for such tumors to express neo-antigens that could expand the tumor antigen-recognizing T cells, poorly differentiated tumors may secrete soluble factors with paracrine activity, favoring tumor growth .
Several studies emphasized on IRF-1 as a transcriptional activator that facilitates a Th1 immune phenotype and leads to tumor infiltration of CD8+ lymphocytes associated with a favorable prognosis in cancer patients [23, 102, 118]. Although the mechanisms leading to IRF-1 activation at the transcriptional level are not known, it is interesting to note that at least in ovarian cancer a convergence is observed between the immune phenotype and the expression of IFN-γ, IL-12 p35 and IL-23 p19  which are powerful stimulators of IRF-1 expression. Moreover, Kryczek et al  observed a combined infiltration of IL-17 expressing CD4+ T cells and CD8+ effector T cells; through synergistic action between IL-17 and IFN-γ expression, Th17 cells were observed to stimulate the expression of CXCL-9 and -10 by ovarian cancer cells as well as tumor infiltrating macrophages in order to recruit more effector T and NK cells to the tumor microenvironment. This combination was observed to positively predict patient outcome in the context of ovarian, colon, hepatocellular and pancreatic carcinoma as well as in melanoma. Altogether this study demonstrated that Th17 cell infiltration in several tumor types was quantitatively and positively correlated with NK cell-mediated innate and adaptive immune responses. The authors investigated the role of various cell subtypes potentially responsible for the induction of this tumor phenotype and identified tumor-associated macrophages as the primary driver through the production of IL-1β, IL23 p19 but not IL-6 and transforming growth factor-β; this effect was, however, neutralized by the presence of T regulatory cells in the same environment .
The importance of a Th1 immune environment has also been observed by Dieu-Nosjean et al.  who observed an association between the presence of tertiary lymphoid organs and better survival outcome in patients with non small cell lung cancer; these tertiary lymph nodes were characterized by the infiltration of B cells, CD8+ and CD4+ T cells expressing T-bet and polarized toward a Th1 phenotype. This is a remarkable observation considering that tertiary lymph nodes are structurally and functionally identical to secondary lymphoid tissues and contain fully activated dendritic cells. It remains unclear why some tumors induce the formation of these tertiary lymphatic structures which are rare in normal conditions and are transiently present only in areas of massive inflammation.
What are the mechanisms leading to constitutive activation of these transcriptional factors in cancer? While strides have been made in the understanding of the activation of the JAK/STAT pathway in leukemia  very little is known about solid cancers. Yet, several candidate mutations have been shown to lead to the activation of innate immune mechanisms in several cancer types including melanoma. Most studies focused on constitutive activation of the master regulator or innate immunity and the cell survival factor NF-k B [121–123]. Since NF-kB and the IRFs are tightly involved in direct and indirect interactions [112, 124–126], it is reasonable to postulate that the same mechanisms may be at the basis of the constitutive activation of STATs and in particular STAT-1 in melanoma. Yet, this information is lacking at the present time and future work should address this question.
Correlation between immune signatures of the tumor microenvironment and systemic immune response
It has been clearly shown that patients with early stage (stage II) or more advanced cancers suffer impaired immune function. The most striking example is decreased activation of ISGs and decreased ability to phosphorylate STAT-1 by circulating immune cells [127–129]. These findings have been reproduced in various cancer types including melanoma, breast and colon cancer. It is important to note that although statistically patients with cancer have strongly reduced immune function compared to normal healthy donors there is great individual variation with overlap of response between patients and normal donors. It is possible that the immune environment of tumors may directly or indirectly influence this systemic phenomenon. It is, however, unknown whether a correlation exists between the immune phenotype of tumors and the responsiveness of peripheral immune cells to immune stimulation. Mortarini et al  observed that impaired STAT activation of T cells did not correlate with frequency of CD4+/CD25+/FoxP3+ T cells at the tumor site, though they did not further compare the global transcriptional patterns of the tumors. Interestingly, they also observed that sera obtained from patients with advanced melanoma inhibited IL-2-dependent STAT activation of normal donor's T cells, and a neutralizing monoclonal antibody to TGF-β1 counteracted such inhibition. Since it is well known that tumors may express this soluble factor it would be interesting to compare the status of activation of various tumors with the behavior of circulating cells to test whether the immune phenotype of tumors drives the systemic alteration of immune function associated with the cancer bearing status. Identification of a correlation would allow indirect immune phenotyping of tumors and consequently predict prognosis by testing circulating cells.
It is becoming clear that tumors can be segregated into at least two categories independently of their histology. Of them one bears a signature consistent with a Th1 type of immune activation which in turn is associated with, lymphocytic infiltrate, better prognosis and enhanced likelihood to respond to therapy. It remains unknown, why this dichotomy occurs, whether it depends on the genetic makeup of individuals bearing the disease or it is due to somatic mutations within cancer cells. It is also unknown, whether these signatures of strong clinical relevance are reflected by changes in the peripheral circulation. We believe that future studies comparing tumor tissue characteristics with the peripheral circulation, along with clinical data will be key to better classify cancers.
- Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, Bedrick JC, Sabet H, Tran T, Xin Y: Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000, 403: 467-578.Google Scholar
- Bittner M, Meltzer P, Chen Y, Jiang E, Seftor E, Hendrix M, Radmacher M, Simon R, Yakhini Z, Ben-Dor A: Molecular classification of cutaneous malignant melanoma by gene expression: shifting from a countinuous spectrum to distinct biologic entities. Nature. 2000, 406: 536-840. 10.1038/35020115.PubMedGoogle Scholar
- Perou CM, Sertle T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, al-Katib A: Molecular portraits of human breast tumorurs. Nature. 2000, 406: 747-752. 10.1038/35021093.PubMedGoogle Scholar
- Mantovani A, Romero P, Palucka AK, Marincola FM: Tumor immunity: effector response to tumor and the influence of the microenvironment. Lancet. 2008, 371: 771-783. 10.1016/S0140-6736(08)60241-X.PubMedGoogle Scholar
- Disis ML: Immune regulation of cancer. J Clin Oncol. 2010, 28: 4531-4538. 10.1200/JCO.2009.27.2146.PubMed CentralPubMedGoogle Scholar
- Kelley T, Beck R, Absi A, Jin T, Pohlman B, Hsi E: Biologic predictors in follicular lymphoma: importance of markers of immune response. Leuk Lymphoma. 2007, 48: 2403-2411. 10.1080/10428190701665954.PubMedGoogle Scholar
- Ho CC, Liao WY, Wang CY, Lu YH, Huang HY, Chen HY, Chan WK, Chen HW, Yang PC: TREM-1 expression in tumor-associated macrophages and clinical outcome in lung cancer. Am J Respir Crit Care Med. 2008, 177: 763-770. 10.1164/rccm.200704-641OC.PubMedGoogle Scholar
- Zhu XD, Zhang JB, Zhuang PY, Zhu HG, Zhang W, Xiong YQ, Wu WZ, Wang L, Tang ZY, Sun HC: High expression of macrophage colony-stimulating factor in peritumoral liver tissue is associated with poor survival after curative resection of hepatocellular carcinoma. J Clin Oncol. 2008, 26: 2707-2716. 10.1200/JCO.2007.15.6521.PubMedGoogle Scholar
- Immunologic signatures of rejection. 2010, New York, NY: SpringerGoogle Scholar
- Wang E, Worschech A, Marincola FM: The immunologic constant of rejection. Trends Immunol. 2008, 29: 256-262. 10.1016/j.it.2008.03.002.PubMedGoogle Scholar
- Yaqub S, Aandahl EM: Inflammation versus adaptive immunity in cancer pathogenesis. Crit Rev Oncog. 2009, 15: 43-63.PubMedGoogle Scholar
- Lin WW, Karin M: A cytokine-mediated link between innate immunity, inflammation, and cancer. J Clin Invest. 2007, 117: 1175-1183. 10.1172/JCI31537.PubMed CentralPubMedGoogle Scholar
- Bedognetti D, Wang E, Sertoli MR, Marincola FM: Gene-expression profiling in vaccine therapy and immunotherapy for cancer. Expert Rev Vaccines. 2010, 9: 555-565. 10.1586/erv.10.55.PubMed CentralPubMedGoogle Scholar
- Bindea G, Mlecnik B, Fridman WH, Pages F, Galon J: Natural immunity to cancer in humans. Curr Opin Immunol. 2010, 22: 215-222. 10.1016/j.coi.2010.02.006.PubMedGoogle Scholar
- Grivennikov SI, Greten FR, Karin M: Immunity, inflammation, and cancer. Cell. 2010, 140: 883-899. 10.1016/j.cell.2010.01.025.PubMed CentralPubMedGoogle Scholar
- Mantovani A, Sica A: Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Curr Opin Immunol. 2010, 22: 231-237. 10.1016/j.coi.2010.01.009.PubMedGoogle Scholar
- Lloyd OC: Regression of malignant melanoma as a manifestation of a cellular immunity response. Proc R Soc Med. 1969, 62: 543-545.PubMed CentralPubMedGoogle Scholar
- Cochran AJ: Histology and prognosis in malignant melanoma. J Pathol. 1969, 97: 459-468. 10.1002/path.1710970305.PubMedGoogle Scholar
- Clemente CG, Mihm MCJ, Bufalino R, Zurrida S, Collini P, Cascinelli N: Prognostic value of tumor infiltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma. Cancer. 1996, 77: 1303-1310. 10.1002/(SICI)1097-0142(19960401)77:7<1303::AID-CNCR12>3.0.CO;2-5.PubMedGoogle Scholar
- Marincola FM, Wang E, Herlyn M, Seliger B, Ferrone S: Tumors as elusive targets of T cell-based active immunotherapy. Trends Immunol. 2003, 24: 335-342.PubMedGoogle Scholar
- Wang E, Miller LD, Ohnmacht GA, Mocellin S, Petersen D, Zhao Y, Simon R, Powell JI, Asaki E, Alexander HR: Prospective molecular profiling of subcutaneous melanoma metastases suggests classifiers of immune responsiveness. Cancer Res. 2002, 62: 3581-3586.PubMed CentralPubMedGoogle Scholar
- Wang E, Panelli MC, Zavaglia K, Mandruzzato S, Hu N, Taylor PR, Seliger B, Zanovello P, Freedman RS, Marincola FM: Melanoma-restricted genes. J Transl Med. 2004, 2: 34-10.1186/1479-5876-2-34.PubMed CentralPubMedGoogle Scholar
- Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, Tosolini M, Camus M, Berger A, Wind P: Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006, 313: 1960-1964. 10.1126/science.1129139.PubMedGoogle Scholar
- Ascierto ML, Kmieciak M, Idowo MO, Manjili R, Zhao Y, Grimes M, Dumur C, Wang E, Ramakrishnan V, Wang X-Y: A signature of immune function genes associated with recurrence-free survival in breast cancer patients. Breast Cancer Res Treat. 2011,Google Scholar
- Sims GP, Rowe DC, Rietdijk ST, Herbst R, Coyle AJ: HMGB1 and RAGE in inflammation and cancer. Annu Rev Immunol. 2010, 28: 367-388. 10.1146/annurev.immunol.021908.132603.PubMedGoogle Scholar
- Gajewski TF: Transcriptional profiling of melanoma as a potential predictive biomarker for response to immunotherapy. Signatures of rejection. Edited by: Wang E, Marincola FM. 2010, New York: Springer, 229-238. FirstGoogle Scholar
- Harlin H, Meng Y, Peterson AC, Zha Y, Tretiakova M, Slingluff C, McKee M, Gajewski TF: Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment. Cancer Res. 2009, 69: 3077-3085.PubMedGoogle Scholar
- Gajewski TF, Zha Y, Thurner B, Schuler G: Association of gene expression profile in melanoma and survival to a dentritic cell-based vaccine. J Clin Oncol. 2009, 27: A9002-Google Scholar
- Brichard VG, Lejeune D: GSK's antigen-specific cancer immunotherapy programme: pilot results leading to Phase III clinical development. Vaccine. 2007, 25 (Suppl 2): B61-B71.PubMedGoogle Scholar
- Louahed J, Grusell O, Gaulis S, Coche T, Eggermont AM, Kruit W, Dreno B, Charion Sileni V, Lehmann F, Brichard VG: Expression of defined genes indentifed by pre-treatment tumor profiling: association with clinical response to GSK MAGE A-3 immunetherapeutic in metastatic melanoma patients. J Clin Oncol. 2008, 26: A9045-Google Scholar
- Sullivan RJ, Hoshida Y, Brunet J, Tahan S, Aldridge J, Kwabi C, Gardiner E, McDermott D, Golub T, Atkins MA: A single center experience with high-dose IL-2 treatment of patients with advanced melanoma and pilot investigation of novel gene expression signature as a predictor of response. J Clin Oncol. 2009, 27: A9003-Google Scholar
- Hamid O, Chasalow SD, Tsuchihashi Z, Alaparthy S, Galbraith S, Berman D: Association of baseline and on-study tumor biopsy markers with clinical activity in patients with advanced melanoma treated with ipilimumab. J Clin Onco. 2009, 27: A9008-Google Scholar
- Moschos SJ, Edington HD, Land SR, Rao UN, Jukic D, Shipe-Spotloe J, Kirkwood JM: Neoadjuvant treatment of regional stage IIIB melanoma with high-dose interferon alfa-2b induces objective tumor regression in association with modulation of tumor infiltrating host cellular immune responses. J Clin Oncol. 2006, 24: 3164-3171. 10.1200/JCO.2005.05.2498.PubMedGoogle Scholar
- Wang W, Edington HD, Rao UN, Jukic DM, Land SR, Ferrone S, Kirkwood JM: Modulation of signal transducers and activators of transcription 1 and 3 signaling in melanoma by high-dose IFNalpha2b. Clin Cancer Res. 2007, 13: 1523-1531. 10.1158/1078-0432.CCR-06-1387.PubMedGoogle Scholar
- Bowman T, Garcia R, Turkson J, Jove R: STATs in oncogenesis. Oncogene. 2000, 19: 2474-2488. 10.1038/sj.onc.1203527.PubMedGoogle Scholar
- Levy DE, Gilliland DG: Divergent roles of STAT1 and STAT5 in malignancy as revealed by gene disruptions in mice. Oncogene. 2000, 19: 2505-2510. 10.1038/sj.onc.1203480.PubMedGoogle Scholar
- Danial NN, Rothman P: JAK-STAT signaling activated by Abl oncogenes. Oncogene. 2000, 19: 2523-2531. 10.1038/sj.onc.1203484.PubMedGoogle Scholar
- Lesinski GB, Trefry J, Brasdovich M, Kondadasula SV, Sackey K, Zimmerer JM, Chaudhury AR, Yu L, Zhang X, Crespin TR: Melanoma cells exhibit variable signal transducer and activator of transcription 1 phosphorylation and a reduced response to IFN-alpha compared with immune effector cells. Clin Cancer Res. 2007, 13: 5010-5019. 10.1158/1078-0432.CCR-06-3092.PubMedGoogle Scholar
- Taylor RC, Patel A, Panageas KS, Busam KJ, Brady MS: Tumor-infiltrating lymphocytes predict sentinel lymph node positivity in patients with cutaneous melanoma. J Clin Oncol. 2007, 25: 869-875. 10.1200/JCO.2006.08.9755.PubMedGoogle Scholar
- Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G, Makrigiannakis A, Gray H, Schlienger K, Liebman MN: Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med. 2003, 348: 203-213. 10.1056/NEJMoa020177.PubMedGoogle Scholar
- Leffers N, Fehrmann RS, Gooden MJ, Schulze UR, Ten Hoor KA, Hollema H, Boezen HM, Daemen T, de JS, Nijman HW: Identification of genes and pathways associated with cytotoxic T lymphocyte infiltration of serous ovarian cancer. Br J Cancer. 2010, 103: 685-692. 10.1038/sj.bjc.6605820.PubMed CentralPubMedGoogle Scholar
- Leffers N, Gooden MJ, de Jong RA, Hoogeboom BN, Ten Hoor KA, Hollema H, Boezen HM, van der Zee AG, Daemen T, Nijman HW: Prognostic significance of tumor-infiltrating T-lymphocytes in primary and metastatic lesions of advanced stage ovarian cancer. Cancer Immunol Immunother. 2009, 58: 449-459. 10.1007/s00262-008-0583-5.PubMedGoogle Scholar
- Sato E, Olson SH, Ahn J, Bundy B, Nishikawa H, Qian F, Jungbluth AA, Frosina D, Gnjatic S, Ambrosone C: Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci USA. 2005, 102: 18538-18543. 10.1073/pnas.0509182102.PubMed CentralPubMedGoogle Scholar
- Kryczek I, Banerjee M, Cheng P, Vatan L, Szeliga W, Wei S, Huang E, Finlayson E, Simeone D, Welling TH: Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments. Blood. 2009, 114: 1141-1149. 10.1182/blood-2009-03-208249.PubMed CentralPubMedGoogle Scholar
- Pages F, Berger A, Camus M, Sanchez-Cabo F, Costes A, Molidor R, Mlecnik B, Kirilovsky A, Nilsson M, Damotte D: Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med. 2005, 353: 2654-2666. 10.1056/NEJMoa051424.PubMedGoogle Scholar
- Camus M, Tosolini M, Mlecnik B, Pages F, Kirilovsky A, Berger A, Costes A, Bindea G, Charoentong P, Bruneval P: Coordination of intratumoral immune reaction and human colorectal cancer recurrence. Cancer Res. 2009, 69: 2685-2693. 10.1158/0008-5472.CAN-08-2654.PubMedGoogle Scholar
- Pages F, Galon J, Dieu-Nosjean MC, Tartour E, Sautes-Fridman C, Fridman WH: Immune infiltration in human tumors, a prognostic factor that should not be ignored. Oncogene. 2009, 29: 1093-1102.PubMedGoogle Scholar
- Pos Z, Galon J: Predictors of favorable outcome in cancer. Immunologic signatures of rejection. Edited by: Wang E, Marincola FM. 2010, New York: Springer, 199-210. 1Google Scholar
- Lee WS, Park S, Lee WY, Yun SH, Chun HK: Clinical impact of tumor-infiltrating lymphocytes for survival in stage II colon cancer. Cancer. 2010, 116: 5188-5199. 10.1002/cncr.25293.PubMedGoogle Scholar
- Naito Y, Saito K, Shiiba K, Ohuchi A, Saigenji K, Nagura H, Ohtani H: CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res. 1998, 58: 3491-3494.PubMedGoogle Scholar
- Oberg A, Samii S, Stenling R, Lindmark G: Different occurrence of CD8+, CD45R0+, and CD68+ immune cells in regional lymph node metastases from colorectal cancer as potential prognostic predictors. Int J Colorectal Dis. 2002, 17: 25-29. 10.1007/s003840100337.PubMedGoogle Scholar
- Correale P, Rotundo MS, Del Vecchio MT, Remondo C, Migali C, Ginanneschi C, Tsang KY, Licchetta A, Mannucci S, Loiacono L: Regulatory (FoxP3+) T-cell tumor infiltration is a favorable prognostic factor in advanced colon cancer patients undergoing chemo or chemoimmunotherapy. J Immunother. 2010, 33: 435-441. 10.1097/CJI.0b013e3181d32f01.PubMedGoogle Scholar
- Tosolini M, Kirilovsky A, Mlecnik B, Fredriksen T, Mauger S, Bindea G, Berger A, Bruneval P, Fridman WH, Pages F: Clinical impact of different classes of infiltrating T cytotoxic and helper cells (Th1, th2, treg, th17) in patients with colorectal cancer. Cancer Res. 2011, 71: 1263-1271. 10.1158/0008-5472.CAN-10-2907.PubMedGoogle Scholar
- Denkert C, Loibl S, Noske A, Roller M, Muller BM, Komor M, Budczies J, rb-Esfahani S, Kronenwett R, Hanusch C: Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol. 2010, 28: 105-113. 10.1200/JCO.2009.23.7370.PubMedGoogle Scholar
- Hsu DS, Kim MK, Balakumaran BS, Acharya CR, Anders CK, Clay T, Lyerly HK, Drake CG, Morse MA, Febbo PG: Immune signatures predict prognosis in localized cancer. Cancer Invest. 2010, 28: 765-773. 10.3109/07357900903095755.PubMed CentralPubMedGoogle Scholar
- Martin DN, Boersma BJ, Yi M, Reimers M, Howe TM, Yfantis HG, Tsai YC, Williams EH, Lee DH, Stephens RM: Differences in the tumor microenvironment between African-American and European-American breast cancer patients. PLoS ONE. 2009, 4: e4531-10.1371/journal.pone.0004531.PubMed CentralPubMedGoogle Scholar
- Singh D, Febbo PG, Ross K, Jackson DG, Manola J, Ladd C, Tamayo P, Renshaw AA, D'Amico AV, Richie JP: Gene expression correlates of clinical prostate cancer behavior. Cancer Cell. 2002, 1: 203-209. 10.1016/S1535-6108(02)00030-2.PubMedGoogle Scholar
- Wallace TA, Prueitt RL, Yi M, Howe TM, Gillespie JW, Yfantis HG, Stephens RM, Caporaso NE, Loffredo CA, Ambs S: Tumor immunobiological differences in prostate cancer between African-American and European-American men. Cancer Res. 2008, 68: 927-936. 10.1158/0008-5472.CAN-07-2608.PubMedGoogle Scholar
- Foye A, Febbo PG: Cancer gene profiling in prostate cancer. Methods Mol Biol. 2010, 576: 293-326.PubMedGoogle Scholar
- Glinsky GV, Glinskii AB, Stephenson AJ, Hoffman RM, Gerald WL: Gene expression profiling predicts clinical outcome of prostate cancer. J Clin Invest. 2004, 113: 913-923.PubMed CentralPubMedGoogle Scholar
- Monsurro' V, Beghelli S, Wang R, Barbi S, Coin S, Di Pasquale G, Bersani S, Castellucci M, Sorio C, Eleuteri S: Anti-viral status segregates two pancreatic adenocarcinoma molecular phenotypes with potential relevance for adenoviral gene therapy. J Transl Med. 2010, 8: 10-10.1186/1479-5876-8-10.Google Scholar
- Dieu-Nosjean MC, Antoine M, Danel C, Heudes D, Wislez M, Poulot V, Rabbe N, Laurans L, Tartour E, de CL: Long-term survival for patients with non-small-cell lung cancer with intratumoral lymphoid structures. J Clin Oncol. 2008, 26: 4410-4417. 10.1200/JCO.2007.15.0284.PubMedGoogle Scholar
- Kawai O, Ishii G, Kubota K, Murata Y, Naito Y, Mizuno T, Aokage K, Saijo N, Nishiwaki Y, Gemma A: Predominant infiltration of macrophages and CD8(+) T Cells in cancer nests is a significant predictor of survival in stage IV nonsmall cell lung cancer. Cancer. 2008, 113: 1387-1395. 10.1002/cncr.23712.PubMedGoogle Scholar
- Klatte T, Seligson DB, Leppert JT, Riggs SB, Yu H, Zomorodian N, Kabbinavar FF, Strieter RM, Belldegrun AS, Pantuck AJ: The chemokine receptor CXCR3 is an independent prognostic factor in patients with localized clear cell renal cell carcinoma. J Urol. 2008, 179: 61-66.PubMedGoogle Scholar
- Shibuya TY, Nugyen N, McLaren CE, Li KT, Wei WZ, Kim S, Yoo GH, Rogowski A, Ensley J, Sakr W: Clinical significance of poor CD3 response in head and neck cancer. Clin Cancer Res. 2002, 8: 745-751.PubMedGoogle Scholar
- Badoual C, Hans S, Rodriguez J, Peyrard S, Klein C, Agueznay NH, Mosseri V, Laccourreye O, Bruneval P, Fridman WH: Prognostic value of tumor-infiltrating CD4+ T-cell subpopulations in head and neck cancers. Clin Cancer Res. 2006, 12: 465-472. 10.1158/1078-0432.CCR-05-1886.PubMedGoogle Scholar
- Sharma P, Shen Y, Wen S, Yamada S, Jungbluth AA, Gnjatic S, Bajorin DF, Reuter VE, Herr H, Old LJ: CD8 tumor-infiltrating lymphocytes are predictive of survival in muscle-invasive urothelial carcinoma. Proc Natl Acad Sci USA. 2007, 104: 3967-3972. 10.1073/pnas.0611618104.PubMed CentralPubMedGoogle Scholar
- Grabenbauer GG, Lahmer G, Distel L, Niedobitek G: Tumor-infiltrating cytotoxic T cells but not regulatory T cells predict outcome in anal squamous cell carcinoma. Clin Cancer Res. 2006, 12: 3355-3360. 10.1158/1078-0432.CCR-05-2434.PubMedGoogle Scholar
- Wenzel J, Tomiuk S, Zahn S, Kusters D, Vahsen A, Wiechert A, Mikus S, Birth M, Scheler M, von BD: Transcriptional profiling identifies an interferon-associated host immune response in invasive squamous cell carcinoma of the skin. Int J Cancer. 2008, 123: 2605-2615. 10.1002/ijc.23799.PubMedGoogle Scholar
- Kandalaft LE, Coukos G: The microenvironment of ovarian cancer: lessons on immune mediated tumor rejection or tolerance. Signatures of rejection. Edited by: Wang E, Marincola FM. 2010, Ney York: Springer, 211-228. FirstGoogle Scholar
- Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y, Yamaguchi K, Higuchi T, Yagi H, Takakura K, Minato N: Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl Acad Sci USA. 2007, 104: 3360-3365. 10.1073/pnas.0611533104.PubMed CentralPubMedGoogle Scholar
- Tomsova M, Melichar B, Sedlakova I, Steiner I: Prognostic significance of CD3+ tumor-infiltrating lymphocytes in ovarian carcinoma. Gynecol Oncol. 2008, 108: 415-420. 10.1016/j.ygyno.2007.10.016.PubMedGoogle Scholar
- Shah CA, Allison KH, Garcia RL, Gray HJ, Goff BA, Swisher EM: Intratumoral T cells, tumor-associated macrophages, and regulatory T cells: association with p53 mutations, circulating tumor DNA and survival in women with ovarian cancer. Gynecol Oncol. 2008, 109: 215-219. 10.1016/j.ygyno.2008.01.010.PubMedGoogle Scholar
- Adams SF, Levine DA, Cadungog MG, Hammond R, Facciabene A, Olvera N, Rubin SC, Boyd J, Gimotty PA, Coukos G: Intraepithelial T cells and tumor proliferation: impact on the benefit from surgical cytoreduction in advanced serous ovarian cancer. Cancer. 2009, 115: 2891-2902. 10.1002/cncr.24317.PubMed CentralPubMedGoogle Scholar
- Clarke B, Tinker AV, Lee CH, Subramanian S, Van de RM, Turbin D, Kalloger S, Han G, Ceballos K, Cadungog MG: Intraepithelial T cells and prognosis in ovarian carcinoma: novel associations with stage, tumor type, and BRCA1 loss. Mod Pathol. 2009, 22: 393-402. 10.1038/modpathol.2008.191.PubMedGoogle Scholar
- Stumpf M, Hasenburg A, Riener MO, Jutting U, Wang C, Shen Y, Orlowska-Volk M, Fisch P, Wang Z, Gitsch G: Intraepithelial CD8-positive T lymphocytes predict survival for patients with serous stage III ovarian carcinomas: relevance of clonal selection of T lymphocytes. Br J Cancer. 2009, 101: 1513-1521. 10.1038/sj.bjc.6605274.PubMed CentralPubMedGoogle Scholar
- Milne K, Kobel M, Kalloger SE, Barnes RO, Gao D, Gilks CB, Watson PH, Nelson BH: Systematic analysis of immune infiltrates in high-grade serous ovarian cancer reveals CD20, FoxP3 and TIA-1 as positive prognostic factors. PLoS ONE. 2009, 4: e6412-10.1371/journal.pone.0006412.PubMed CentralPubMedGoogle Scholar
- Blegen H, Einhorn N, Sjovall K, Roschke A, Ghadimi BM, McShane LM, Nilsson B, Shah K, Ried T, Auer G: Prognostic significance of cell cycle proteins and genomic instability in borderline, early and advanced stage ovarian carcinomas. Int J Gynecol Cancer. 2000, 10: 477-487. 10.1046/j.1525-1438.2000.00077.x.PubMedGoogle Scholar
- Kmieciak M, Knutson KL, Dumur CI, Manjili MH: HER-2/neu antigen loss and relapse of mammary carcinoma are actively induced by T cell-mediated anti-tumor immune responses. Eur J Immunol. 2007, 37: 675-685. 10.1002/eji.200636639.PubMed CentralPubMedGoogle Scholar
- Kmieciak M, Payne KK, Idowu MO, Grimes MM, Graham L, Ascierto ML, Wang E, Wang XY, Bear HD, Manjili MH: Tumor escape and progression of HER-2/neu negative breast cancer under immune pressure. J Transl Med. 2011, 9: 35-10.1186/1479-5876-9-35.PubMed CentralPubMedGoogle Scholar
- Kuroda H, Tamaru J, Sakamoto G, Ohnisi K, Itoyama S: Immunophenotype of lymphocytic infiltration in medullary carcinoma of the breast. Virchows Arch. 2005, 446: 10-14. 10.1007/s00428-004-1143-9.PubMedGoogle Scholar
- Buckowitz A, Knaebel HP, Benner A, Blaker H, Gebert J, Kienle P, von Knebel DM, Kloor M: Microsatellite instability in colorectal cancer is associated with local lymphocyte infiltration and low frequency of distant metastases. Br J Cancer. 2005, 92: 1746-1753. 10.1038/sj.bjc.6602534.PubMed CentralPubMedGoogle Scholar
- Kooi S, Zhang HZ, Patenia R, Edwards CL, Platsoucas CD, Freedman RS: HLA class I expression on human ovarian carcinoma cells correlates with T-cell infiltration in vivo and T-cell expansion in vitro in low concentrations of recombinant interleukin-2. Cell Immunol. 1996, 174: 116-128. 10.1006/cimm.1996.0301.PubMedGoogle Scholar
- Sallusto F, Lenig D, Forster R, Lipp M, Lanzavecchia A: Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature. 1999, 401: 659-660. 10.1038/44309.Google Scholar
- Wolf AM, Rumpold H, Reimer D, Marth C, Zeimet AG, Wolf D: High IL-12 p35 and IL-23 p19 mRNA expression is associated with superior outcome in ovarian cancer. Gynecol Oncol. 2010, 118: 244-250. 10.1016/j.ygyno.2010.05.024.PubMedGoogle Scholar
- Salama P, Phillips M, Grieu F, Morris M, Zeps N, Joseph D, Platell C, Iacopetta B: Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol. 2009, 27: 186-192. 10.1200/JCO.2008.18.7229.PubMedGoogle Scholar
- Frey DM, Droeser RA, Viehl CT, Zlobec I, Lugli A, Zingg U, Oertli D, Kettelhack C, Terracciano L, Tornillo L: High frequency of tumor-infiltrating FOXP3(+) regulatory T cells predicts improved survival in mismatch repair-proficient colorectal cancer patients. Int J Cancer. 2010, 126: 2635-2643.PubMedGoogle Scholar
- Zlobec I, Karamitopoulou E, Terracciano L, Piscuoglio S, Iezzi G, Muraro MG, Spagnoli G, Baker K, Tzankov A, Lugli A: TIA-1 cytotoxic granule-associated RNA binding protein improves the prognostic performance of CD8 in mismatch repair-proficient colorectal cancer. PLoS ONE. 2010, 5: e14282-10.1371/journal.pone.0014282.PubMed CentralPubMedGoogle Scholar
- Schwartzentruber DJ, Lawson DH, Richards JM, Conry RM, Miller DM, Treisman J, Gailani F, Riley L, Conlon K, Pockaj B: gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma. N Engl J Med. 2011, 364: 2119-2127. 10.1056/NEJMoa1012863.PubMed CentralPubMedGoogle Scholar
- Hoffmann P, Boeld TJ, Eder R, Huehn J, Floess S, Wieczorek G, Olek S, Dietmaier W, Andreesen R, Edinger M: Loss of FOXP3 expression in natural human CD4+CD25+ regulatory T cells upon repetitive in vitro stimulation. Eur J Immunol. 2009, 39: 1088-1097. 10.1002/eji.200838904.PubMedGoogle Scholar
- Walker MR, Kasprowicz DJ, Gersuk VH, Benard A, Van LM, Buckner JH, Ziegler SF: Induction of FoxP3 and acquisition of T regulatory activity by stimulated human CD4+. J Clin Invest. 2003, 112: 1437-1443.PubMedGoogle Scholar
- Roncador G, Brown PJ, Maestre L, Hue S, Martinez-Torrecuadrada JL, Ling KL, Pratap S, Toms C, Fox BC, Cerundolo V: Analysis of FOXP3 protein expression in human CD4+CD25+ regulatory T cells at the single-cell level. Eur J Immunol. 2005, 35: 1681-1691. 10.1002/eji.200526189.PubMedGoogle Scholar
- Zuo T, Wang L, Morrison C, Chang X, Zhang H, Li W, Liu Y, Wang Y, Liu X, Chan MW: FOXP3 is an X-linked breast cancer suppressor gene and an important repressor of the HER-2/ErbB2 oncogene. Cell. 2007, 129: 1275-1286. 10.1016/j.cell.2007.04.034.PubMed CentralPubMedGoogle Scholar
- Wang L, Liu R, Li W, Chen C, Katoh H, Chen GY, McNally B, Lin L, Zhou P, Zuo T: Somatic single hits inactivate the X-linked tumor suppressor FOXP3 in the prostate. Cancer Cell. 2009, 16: 336-346. 10.1016/j.ccr.2009.08.016.PubMed CentralPubMedGoogle Scholar
- Karanikas V, Speletas M, Zamanakou M, Kalala F, Loules G, Kerenidi T, Barda AK, Gourgoulianis KI, Germenis AE: Foxp3 expression in human cancer cells. J Transl Med. 2008, 6: 19-10.1186/1479-5876-6-19.PubMed CentralPubMedGoogle Scholar
- Wang Y, Liu DP, Chen PP, Koeffler HP, Tong XJ, Xie D: Involvement of IFN regulatory factor (IRF)-1 and IRF-2 in the formation and progression of human esophageal cancers. Cancer Res. 2007, 67: 2535-2543. 10.1158/0008-5472.CAN-06-3530.PubMedGoogle Scholar
- Ladoire S, Mignot G, Dabakuyo S, Arnould L, Apetoh L, Rebe C, Coudert B, Martin F, Bizollon MH, Vanoli A: In situ immune response after neoadjuvant chemotherapy for breast cancer predicts survival. J Pathol. 2011, 224: 389-400. 10.1002/path.2866.PubMedGoogle Scholar
- 't Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M, Peterse HL, van der KK, Marton MJ, Witteveen AT: Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002, 415: 530-536. 10.1038/415530a.PubMedGoogle Scholar
- Mahmoud SM, Paish EC, Powe DG, Macmillan RD, Grainge MJ, Lee AH, Ellis IO, Green AR: Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. J Clin Oncol. 2011, 29: 1949-1955. 10.1200/JCO.2010.30.5037.PubMedGoogle Scholar
- Giltnane JM, Rimm DL: Technology insight: Identification of biomarkers with tissue microarray technology. Nat Clin Pract Oncol. 2004, 1: 104-111. 10.1038/ncponc0046.PubMedGoogle Scholar
- Hassan S, Ferrario C, Mamo A, Basik M: Tissue microarrays: emerging standard for biomarker validation. Curr Opin Biotechnol. 2008, 19: 19-25. 10.1016/j.copbio.2007.10.009.PubMedGoogle Scholar
- Zeimet AG, Reimer D, Wolf D, Fiegl H, Concin N, Wiedemair A, Wolf AM, Rumpold H, Muller-Holzner E, Marth C: Intratumoral interferon regulatory factor (IRF)-1 but not IRF-2 is of relevance in predicting patient outcome in ovarian cancer. Int J Cancer. 2009, 124: 2353-2360. 10.1002/ijc.24214.PubMedGoogle Scholar
- Selleri S, Deola S, Pos Z, Jin P, Worschech A, Slezak S, Rumio C, Panelli MC, Maric D, Stroncek DF: GM-CSF/IL-3/IL-5 receptor common B chain (CD131) as a biomarker of antigen-stimulated CD8+ T cells. J Transl Med. 2008, 6: 17-10.1186/1479-5876-6-17.PubMed CentralPubMedGoogle Scholar
- Lesinski GB, Kondadasula SV, Crespin T, Shen L, Kendra K, Walker M, Carson WE: Multiparametric flow cytometric analysis of inter-patient variation in STAT1 phosphorylation following interferon Alfa immunotherapy. J Natl Cancer Inst. 2004, 96: 1331-1342. 10.1093/jnci/djh252.PubMedGoogle Scholar
- Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, Evdemon-Hogan M, Conejo-Garcia JR, Zhang L, Burow M: Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med. 2004, 10: 942-949. 10.1038/nm1093.PubMedGoogle Scholar
- Buckanovich RJ, Facciabene A, Kim S, Benencia F, Sasaroli D, Balint K, Katsaros D, O'Brien-Jenkins A, Gimotty PA, Coukos G: Endothelin B receptor mediates the endothelial barrier to T cell homing to tumors and disables immune therapy. Nat Med. 2008, 14: 28-36. 10.1038/nm1699.PubMedGoogle Scholar
- Kandalaft LE, Facciabene A, Buckanovich RJ, Coukos G: Endothelin B receptor, a new target in cancer immune therapy. Clin Cancer Res. 2009, 15: 4521-4528. 10.1158/1078-0432.CCR-08-0543.PubMed CentralPubMedGoogle Scholar
- Manjili MH: Revisiting cancer immunoediting by understanding cancer immune complexity. J Pathol. 2011, 224: 5-9. 10.1002/path.2865.PubMed CentralPubMedGoogle Scholar
- Gajewski TF, Fuertes M, Spaapen R, Zheng Y, Kline J: Molecular profiling to identify relevant immune resistance mechanisms in the tumor microenvironment. Curr Opin Immunol. 2010Google Scholar
- Suk K, Kim YH, Chang I, Kim JY, Choi YH, Lee KY, Lee MS: IFNalpha sensitizes ME-180 human cervical cancer cells to TNFalpha-induced apoptosis by inhibiting cytoprotective NF-kappaB activation. FEBS Lett. 2001, 495: 66-70. 10.1016/S0014-5793(01)02335-3.PubMedGoogle Scholar
- Suk K, Chang I, Kim YH, Kim S, Kim JY, Kim H, Lee MS: Interferon gamma (IFNgamma) and tumor necrosis factor alpha synergism in ME-180 cervical cancer cell apoptosis and necrosis. IFNgamma inhibits cytoprotective NF-kappa B through STAT1/IRF-1 pathways. J Biol Chem. 2001, 276: 13153-13159. 10.1074/jbc.M007646200.PubMedGoogle Scholar
- Tamura T, Yanai H, Savitsky D, Taniguchi T: The IRF family transcription factors in immunity and oncogenesis. Annu Rev Immunol. 2008, 26: 535-584. 10.1146/annurev.immunol.26.021607.090400.PubMedGoogle Scholar
- Lee JH, Chun T, Park SY, Rho SB: Interferon regulatory factor-1 (IRF-1) regulates VEGF-induced angiogenesis in HUVECs. Biochim Biophys Acta. 2008, 1783: 1654-1662. 10.1016/j.bbamcr.2008.04.006.PubMedGoogle Scholar
- Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G: Immunological aspects of cancer chemotherapy. Nat Rev Immunol. 2008, 8: 59-73. 10.1038/nri2216.PubMedGoogle Scholar
- Wang T, Niu G, Kortylewski M, Burdelya L, Shain K, Zhang S, Bhattacharya R, Gabrilovich D, Heller R, Coppola D: Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat Med. 2004, 10: 48-54. 10.1038/nm976.PubMedGoogle Scholar
- Jin P, Marincola FM, Wang E: Cytokine polymorphism and its possible impact on cancer. Immunol Res. 2004,Google Scholar
- Hancock WW, Wang L, Ye Q, Han R, Lee I: Chemokines and their receptors as markers of allograft rejection and targets for immunosuppression. Curr Opin Immunol. 2003, 15: 479-486. 10.1016/S0952-7915(03)00103-1.PubMedGoogle Scholar
- Callahan MJ, Nagymanyoki Z, Bonome T, Johnson ME, Litkouhi B, Sullivan EH, Hirsch MS, Matulonis UA, Liu J, Birrer MJ: Increased HLA-DMB expression in the tumor epithelium is associated with increased CTL infiltration and improved prognosis in advanced-stage serous ovarian cancer. Clin Cancer Res. 2008, 14: 7667-7673. 10.1158/1078-0432.CCR-08-0479.PubMed CentralPubMedGoogle Scholar
- Marth C, Fiegl H, Zeimet AG, Muller-Holzner E, Deibl M, Doppler W, Daxenbichler G: Interferon-gamma expression is an independent prognostic factor in ovarian cancer. Am J Obstet Gynecol. 2004, 191: 1598-1605. 10.1016/j.ajog.2004.05.007.PubMedGoogle Scholar
- Constantinescu SN, Girardot M, Pecquet C: Mining for JAK-STAT mutations in cancer. Trends Biochem Sci. 2008, 33: 122-131. 10.1016/j.tibs.2007.12.002.PubMedGoogle Scholar
- Ueda Y, Richmond A: NF-kappaB activation in melanoma. Pigment Cell Res. 2006, 19: 112-124. 10.1111/j.1600-0749.2006.00304.x.PubMed CentralPubMedGoogle Scholar
- Lin Y, Bai L, Chen W, Xu S: The NF-kappaB activation pathways, emerging molecular targets for cancer prevention and therapy. Expert Opin Ther Targets. 2010, 14: 45-55. 10.1517/14728220903431069.PubMed CentralPubMedGoogle Scholar
- Prasad S, Ravindran J, Aggarwal BB: NF-kappaB and cancer: how intimate is this relationship. Mol Cell Biochem. 2010, 336: 25-37. 10.1007/s11010-009-0267-2.PubMed CentralPubMedGoogle Scholar
- Escalante CR, Yie J, Thanos D, Aggarwal AK: Structure of IRF-1 with bound DNA reveals determinants of interferon regulation. Nature. 1998, 391: 103-106. 10.1038/34224.PubMedGoogle Scholar
- Paun A, Pitha PM: The IRF family, revisited. Biochimie. 2007, 89: 744-753. 10.1016/j.biochi.2007.01.014.PubMed CentralPubMedGoogle Scholar
- Shultz DB, Rani MR, Fuller JD, Ransohoff RM, Stark GR: Roles of IKK-beta, IRF1, and p65 in the activation of chemokine genes by interferon-gamma. J Interferon Cytokine Res. 2009, 29: 817-824. 10.1089/jir.2009.0034.PubMed CentralPubMedGoogle Scholar
- Critchley-Thorne RJ, Yan N, Nacu S, Weber J, Holmes SP, Lee PP: Down-regulation of the interferon signaling pathway in T lymphocytes from patients with metastatic melanoma. PLoS Med. 2007, 4: e176-10.1371/journal.pmed.0040176.PubMed CentralPubMedGoogle Scholar
- Critchley-Thorne RJ, Simons D, Yan N, Miyahira A, Dirbas F, Johnson D, Swetter S, Carlson R, Fisher G, Koong A: Impaired interferon signaling is a common immune defect in human cancer. Proc Natl Acad Sci USA. 2009, 106: 9010-9015. 10.1073/pnas.0901329106.PubMed CentralPubMedGoogle Scholar
- Mortarini R, Vegetti C, Molla A, Arienti F, Ravagnani F, Maurichi A, Patuzzo R, Santinami M, Anichini A: Impaired STAT phosphorylation in T cells from melanoma patients in response to IL-2: association with clinical stage. Clin Cancer Res. 2009, 15: 4085-4094. 10.1158/1078-0432.CCR-08-3323.PubMedGoogle Scholar
- Pages F, Kirilovsky A, Mlecnik B, Asslaber M, Tosolini M, Bindea G, Lagorce C, Wind P, Bruneval P, Zatloukal K: The in situ cytotoxic and memory T cells predict outcome in early-stage colerectal cancer patients. J Clin Oncol. 2009,Google Scholar
- Schumacher K, Haensch W, Roefzaad C, Schlag PM: Prognostic significance of activated CD8(+) T cell infiltrations within esophageal carcinomas. Cancer Res. 2001, 61: 3932-3936.PubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.