- Open Access
Induction of antitumor immunity through xenoplacental immunization
© Zhong et al; licensee BioMed Central Ltd. 2006
Received: 03 April 2006
Accepted: 25 May 2006
Published: 25 May 2006
Historically cancer vaccines have yielded suboptimal clinical results. We have developed a novel strategy for eliciting antitumor immunity based upon homology between neoplastic tissue and the developing placenta. Placenta formation shares several key processes with neoplasia, namely: angiogenesis, activation of matrix metalloproteases, and active suppression of immune function. Immune responses against xenoantigens are well known to break self-tolerance. Utilizing xenogeneic placental protein extracts as a vaccine, we have successfully induced anti-tumor immunity against B16 melanoma in C57/BL6 mice, whereas control xenogeneic extracts and B16 tumor extracts where ineffective, or actually promoted tumor growth, respectively. Furthermore, dendritic cells were able to prime tumor immunity when pulsed with the placental xenoantigens. While vaccination-induced tumor regression was abolished in mice depleted of CD4 T cells, both CD4 and CD8 cells were needed to adoptively transfer immunity to naïve mice. Supporting the role of CD8 cells in controlling tumor growth are findings that only freshly isolated CD8 cells from immunized mice were capable of inducing tumor cell caspases-3 activation ex vivo. These data suggest feasibility of using xenogeneic placental preparations as a multivalent vaccine potently targeting not just tumor antigens, but processes that are essential for tumor maintenance of malignant potential.
For successful pregnancy to occur, establishment of hemochorial placentation is essential. The process of placenta formation involves tissue morphogenesis , activation of matrix metalloproteases , and active suppression of immune function [3, 4]. Placental expression of matrix metalloproteases (MMPs), [5, 6], Fas ligand (Fas-L)  and immune suppressants such as DAF , CD55 , IL-10 , and VEGF  are involved in generating a suitable placental microenvironment for healthy pregnancy. The expression of the same molecules by tumor cells is associated with poor prognosis and endows a competitive advantage to neoplastic cells [12–16]. In addition, various tumor antigens such as hCG, MAGE, BAGE are expressed in placental tissue [17, 18].
Induction of immune responses towards self-proteins associated with tumor progression is a possible therapeutic approach to cancer. While administration of syngeneic or allogeneic proteins induces poor immune response, it is reported that administration of xenogeneic homologous proteins are capable of eliciting immunity against the endogenous self-protein. Vaccination with xenogeneic FGF-R , VEGF , PAP , and MMP-2  resulted in potent immunological control of tumors that depend on these molecules for survival. Indeed, vaccination with xenogeneic endothelial cells has been used to block tumor angiogenesis in the recipient in an effective manner [23–25].
Based on the above rationale, we hypothesized that immunization with xenogeneic placental extracts would result in a potent immune response to the inhibitory cytokines, MMPs, and immune suppressive factors produced by the cancer. The success of this approach would pave the way for cancer vaccines effective against a wide variety of tumors since it does not involve targeting tissue-specific markers, but molecules essential for the existence and propagation of the tumor. Accordingly, in this study we sought to demonstrate feasibility of such an approach using the B16 murine model of melanoma, an accepted model of immunotherapy. We have demonstrated the ability of a single immunization to inhibit tumor growth in a CD4+ T cell dependent manner and the need for both CD4 and CD8 T cells to adoptively transfer immunity. Furthermore immunization using syngeneic dendritic cells pulsed with xenogenic placental extracts induced immunity at the time of tumor inoculation in a semi-therapeutic model. These data demonstrate feasibility of using this novel antigenic source as a starting point for therapeutic vaccine development.
Materials and methods
Female C57/BL6 mice (The Jackson Laboratories, Bar Harbor, ME), 5 wk of age, were kept in filter-top cages at the Animal Care and Veterinary Services Facility, the University of Western Ontario according to the Canadian Council for Animal Care Guidelines. Mice were fed by food and water ad libitum and allowed to settle for 2 wk before initiation of experimentations
Preparation of xenogeneic placental extract and controls
Porcine placental tissue was obtained from delivering sows and washed in sterile phosphate buffered saline (PBS) containing 5% penicillin streptomycin mixture and placed on ice for transportation. Vascularized placental tissue was homogenized with a tissue grinder and exposed to 4 freeze-thaw cycles alternating from liquid nitrogen to 42 Celsius water bath. Cell debris was pelleted by centrifugation at 1500 g for 45 minutes. Supernatant was collected and sterilized with 0.2 micron Millipore filters. Total protein concentration was determined using the Bradford Assay (BioRad). For control tissue, porcine liver and B16 melanoma cell line proteins were isolated using identical protocol. Experiments utilizing allogeneic placental extracts were performed using term-BALB/c placental extracts prepared in a manner identical to the xenogeneic placental extracts. The whole protein preparations were dissolved into sterile, injection-grade PBS at a concentration of 2 mg/ml, and injections of 50 uL (total mass 10 ug) were performed subcutaneously into C57/BL6 mice 7 days before tumor challenge.
Pulsing of dendritic cells
At Day 0, bone marrow cells were flushed from the femurs and tibias of C57/BL6 mice, washed and cultured in 6-well plates (Corning, NY) at 4 × 106 cells/well in 4 ml of complete medium (RPMI 1640 supplemented with 2 mM L-glutamine, 100 U/ml penicillin, 100 μg of streptomycin, 50 μM 2-ME, and 10% FCS (all from Life Technologies, Ontario, Canada) supplemented with recombinant GM-CSF (10 ng/ml; PeproTech, Rocky Hill, NJ) and recombinant mouse IL-4 (10 ng/ml; PeproTech). All cultures were incubated at 37°C in 5% humidified CO2. Non-adherent cells were removed after 48 h of culture (Day 2) and fresh medium was added. After 7 days of culture, >90% of the cells expressed the characteristic DC-specific marker CD11c asdetermined by FACS. DC were washed and plated in 24-well platesat a concentration of 2 × 105 cells/well in 400 μl ofserum-free RPMI 1640. Pulsing with XPE and/or OVA was performed by addition of said antigens at a concentration of 10 ug/ml for 24 hours.
Proliferative recall responses to XPE and ovalbumin in immunized mice were assessed by sacrificing C57/BL6 mice, 14 days after immunization with antigen-loaded DC. T cells were purified from suspensions of lymph nodes using CD4+ T cell column (R&D Systems) after washing in PBS. Purified T cells were cultured in 96 well plates with irradiated syngeneic splenocytes in triplicate and mixed with serial dilutions of OVA at concentrations ranging from 0–10 ug/ml. Following a 72-h incubation, 1 μCi of [3H]thymidine (Amersham) was added to each well for 16 h. Using an automated cell harvester, the cells were collected onto glass microfiber filter, and the radioactive labeling incorporation was measured by a Wallac Betaplate liquid scintillation counter.
Detection of CD8 T cell mediated caspase-3 activation
Flow cytometry was used to assess ability of CD8 cells to mediate induction of apoptosis pathway in target cells. Briefly, CD8 T cells were isolated from spleens of experimental and control mice on day 8 after immunization using the Murine CD8 Subset Column Kit (R&D Systems, Minneapolis, MN) according to the manufacturer's instructions. Cultures were prepared in RPMI 1640 medium (Invitrogen, CA) supplemented with 10% fetal bovine serum (FBS), 100 U penicillin G, 100 μg/ml of streptomycin sulfate and 2 mM L-glutamine. To test the CD8 effector function in terms of caspases-3 activating ability, the freshly isolated CD8 cells (effector cells, E) were mixed with target tumor cells (T) labeled with CellTracker Green dye at E:T ratios equal to 50:1, 25:1, 12.5:1, 6.25:1. As targets we used B16 melanoma cells, porcine splenocytes, murine splenocytes, as well as porcine trophoblasts and murine trophoblasts isolated by enzymatic dissociation with collagenase I and percoll density sedimentation as described [26, 27]. After a 3 hour co-incubation, the effector:target mixtures were washed, fixed and permeabilized before staining with PE-labeled anti-Caspase-3 antibodies (BD Pharmingen, CA). After incubation (20 minutes, 4°C) and washing, the number of activated caspase-3 positive apoptotic cells was detected in CellTracker Green-positive target cells population and then the percentage of cells with activated caspases-3 were calculated using CellQuest software.
The supernatants from recall response T cell cultures were harvested at 24 hour incubation and assessed for IFN-γ and IL-4 by ELISA. Cytokine-specific ELISA (Endogen, Rockford, IL) was used for detecting cytokine concentrations in culture supernatants according to the manufacturer's instructions using a Benchmark Microplate Reader (Bio-Rad, Hercules, CA).
B16 tumor model
For induction of tumor growth, 5 × 105 B16 American Type Culture Collection (Manassas, VA) cells were injected subcutaneously into the hind limb flank. Tumor growth was assessed every 3 days by two measurements of perpendiculardiameters by a caliper, and animals were sacrificed when tumors reached a size of 1 cm in any direction. Tumor volume was calculated by the following formula: (the shortestdiameter2 × the longest diameter)/2
Groups of 8 mice immunized with either xenogeneic placental extract, saline, or control xenogeneic liver placental extract were challenged on day 7 with 5 × 105 B16 cells and observed for an additional 18 days. Subsequently, mice were sacrificed and CD4+, and CD8+ cells were isolated using the Murine CD4 Subset Column Kit, and Murine CD8 Subset Column Kit (R&D Systems), respectively. 107 CD4 and/or CD8 cells were transferred to naïve C57/BL6 mice intravenously at time of tumor challenge with 5 × 105 B16 cells.
Data is presented in a primarily descriptive fashion. All experiments used 4–8 mice per treatment group and were repeated at least 3 times. For some experiments differences in tumor size were analyzed using the two-tailed Student's t test with significance determined at p < 0.05.
Prophylaxis of tumor growth by Xenogeneic Placental Extract (XPE)
XPE synergy with B16 vaccine
Dendritic cell immunization
XPE-induced protection is CD4+ T cell dependent
XPE-induced anti-tumor response is associated with generation of CD8 cells capable of activating caspase-3
Transfer of XPE-induced protection requires CD4 and CD8 T cells
It has been reported that immunization with placental extracts possesses clinical efficacy toward a variety of tumor types clinically, as previously reviewed by Harandi . Unfortunately, randomized clinical trials have not been performed and the data is at best anecdotal. Conceptually, vaccination with placental extracts would be capable of eliciting immunological responses not only to marker antigens shared between the placenta and neoplasia such as hCG, MAGE, BAGE [17, 18], but also to functional proteins that tumors require to maintain malignancy. For example, stimulation of immunity against MMPs found on placental tissue may theoretically cause inhibition of tumor MMP activity and reduction in tissue invasiveness and metastasis. Indeed, while others have previously demonstrated inhibition of tumor growth after immunization with MMP-2 , it was recently observed that human melanoma cells uptake MMP-2 in an alpha v beta3-dependent manner, and present peptides thereof to HLA*0201-restricted T cells .
In addition to MMPs, placental formation in normal pregnancy is dependent on two other main functional activities, the first being suppression of immune responses in a selective or semi-selective manner, and the second being ability to rapidly induce angiogenesis to form the appropriate interface for maternal-fetal nutrient transmission. It is established that tumors also require induction of immune suppression, as well as angiogenesis for their survival, and indeed the higher immune suppression and angiogenesis found in tumors, the worse the patient prognosis is. The sharing between placental cells and cancer cells of immune suppression/immune evasion molecules such as fas ligand (Fas-L) , DAF , CD55 , IL-10 , MICA , HLA-G and indolamine 2,3 dioxygenase , as well as molecules of angiogenesis such as VEGF , placental growth factor , angiopoietin , FGF, EGF, and TGF-beta  suggests not only a functional, but also a molecular homology between placenta and cancer cells.
The knowledge that placental extracts may be stimulatory of anticancer immune responses has been postulated to account for the lower incidence of certain tumors in multi-parous women . Indeed older studies using placental immunization in mouse models have demonstrated some efficacy in tumor inhibition as reviewed by Harandi . Our approach to utilization of placental extracts was mindful of the Immunostimulatory Hypothesis proposed by Prehn , suggesting that the immune response may in some cases actually contribute to tumor growth. With this in mind, we sought to specifically use a potent means of inducing a "danger signal" while concurrently providing a multivalent tumor antigenic source. Based on the hyperacute nature of xenogenic rejection , the multitude of data supporting superior breaking of tolerance using xenogenic variants of self-proteins [44–46], and the fact that autoimmune disease is evoked only by xenogeneic self antigens in animal models of autoimmune disease [47, 48], we decided to immunize C57/BL6 mice with xenogenic placental extracts (XPE) and observe antitumor effects.
We have demonstrated that immunization with a preparation of xenogenic placental extract induced a CD4-dependent immune response capable of inhibiting growth of B16 melanoma cells in the C57/BL6 mouse. Demonstration of CD8 activity in the induction of tumor regression was performed in experiments showing that freshly isolated CD8 cells from immunized mice were capable of inducing both tumor cell, as well as xenogeneic trophoblast apoptosis cascades. Immune-mediated clearance seemed to be specific to the XPE since immunization with control porcine liver extracts did not mediate protection. Additionally, the xenogeneic component of XPE seems to be critical since apoptosis-inducing cells were not detected in mice immunized with allogeneic placental extracts. Although we did not elucidate specific antigenic targets of xenoplacental immunization, preliminary data seems to suggest that inhibition of neoangiogenesis may be one of the potent mechanisms. Studies using purified immunoglobulin from XPE immunized mice demonstrate the ability to inhibit in vitro proliferation of endothelial cells. This work is still in progress and will be reported in a subsequent publication.
The ability of XPE to inhibit tumor growth may not be surprising given the high concentration of endothelial cells in placental tissue, and previous reports that immunization with xeno-endothelial cells causes anticancer responses [25, 49]. However, the potent ability of XPE to act as a Th1 and Th2 adjuvant for HEL-specific recall responses is surprising. Indeed it has been speculated that xenogenic antigens may intrinsically be stimulatory of dendritic cell function, however to our knowledge, this is the first report actually demonstrating this. Future experiments will assess the effect of XPE on dendritic cell maturation, and function in vitro in order to identify whether the XPE was actually giving a direct signal to dendritic cells, or whether the augmentation of DC activation occurs after the re-introduction of pulsed DC in vivo. Nevertheless, it appears that XPE has a potent immune enhancing property since it was able to potentiate the anti-B16 response of the B16 lysate vaccine in addition to the anti-HEL response.
Although numerous tumor antigens are currently under intense investigation, the ability for a multi-epitopic composition such as XPE to induce immunity that is transferable to naïve recipients is somewhat surprising given the lack of immunological adjuvants or multi-injection regimens used in other studies. In conclusion, XPE appears to be a potent stimulator of anticancer immune responses in a CD4 and CD8 T cell dependent manner. The characterization of both cross-reactive tumor antigens, as well as the apparent ability to act as an immunological adjuvant, will provide interesting new avenues of research, with the possibility of developing novel, clinically applicable therapeutics from a relatively benign antigenic source.
The authors express many thanks to Carmen Molinaro for unwavering support and contributions that were essential to success of this study. We also thank Guillermo Arreaza from the NIH for critical reviews and comments.
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