T and NK cells: two sides of tumor immunoevasion
© Fruci et al.; licensee BioMed Central Ltd. 2013
Received: 21 November 2012
Accepted: 30 January 2013
Published: 4 February 2013
Natural Killer (NK) cells are known to reject several experimental murine tumors, but their antineoplastic activity in humans is not generally agreed upon, as exemplified by an interesting correspondence recently appeared in Cancer Research. In the present commentary, we join the discussion and bring to the attention of the readers of the Journal of Translational Medicine a set of recent, related reports. These studies demonstrate that effectors of the adaptive and innate immunity need to actively cooperate in order to reject tumors and, conversely, tumors protect themselves by dampening both T and NK cell responses. The recently reported ability of indoleamine 2,3-dioxygenase (IDO) and prostaglandin E2 (PGE2) expressed by melanoma cells to down-regulate activating NK receptors is yet another piece of evidence supporting combined and highly effective T/NK cell disabling. Major Histocompatibility Complex class I (MHC-I) molecules, including Human Leukocyte Antigen E (HLA-E), represent another class of shared activating/inhibitory ligands. Ongoing clinical trials with small molecules interfering with IDO and PGE2 may be exploiting an immune bonus to control cancer. Conversely, failure to simultaneously engage effectors of both the innate and the adaptive immunity may contribute to explain the limited clinical efficacy of T cell-only vaccination trials. Shared (T/NK cells) natural immunosuppressants and activating/inhibitory ligands expressed by tumor cells may provide mechanistic insight into impaired gathering and function of immune effectors at the tumor site.
A report published on March 15, and the following correspondence published October 11, 2012 in Cancer Research[1–3] revamp the old vexing question of Natural Killer (NK) cells and tumors. Do NK cells reject human tumors? Do they positively influence clinical outcome? Do tumors bother at all evading NK cells? In their original paper, Pietra and colleagues appear to answer yes to all these questions. They show that melanoma cells produce indoleamine 2,3-dioxygenase (IDO) and prostaglandin E2 (PGE2), two natural immunosuppressants that down-regulate activating NK receptors. Whereas this is highly suggestive of an active immunoevasion strategy, in a subsequent letter to the Editor Sconocchia et al. emphasize the poor NK cell infiltration of most tumor lesions, including melanoma, a finding that is suggested to question the role of NK cells in contrasting solid tumor progression in humans. In their conclusive authors’ reply, Pietra et al. attempt to reconcile these views. In extreme synthesis, they argue that NK cell disarmament and poor infiltration may be two sides of the same coin.
This interpretation is fully agreeable, but in our opinion it enlightens a particular case of a more general and widely inclusive concept. As thoroughly documented by Shanker and Marincola in a recent review, tumor rejection is a two-way, cooperative endeavor involving both innate and adaptive immunity: T and NK cells in the first place, but most certainly also other immune cells, including dendritic cells, macrophages, and neutrophils. This is particularly evident in certain murine experimental tumor systems in which a direct communication axis has been identified between T and NK cells[5, 6]. Somewhat reciprocal to this concept, we recently reviewed the available evidence that tumor immunoevasion requires the simultaneous derangement of both T and NK cells, as shown by the analysis of Major Histocompatibility Complex class I (MHC-I) phenotypes of human tumors. Herein, we go on and argue that the function of a core set of shared mechanisms impairing T/NK cell functions begins to be unraveled. IDO, PGE2 and self MHC-I may be the prototypes of shared (T/NK) immunoevasion ligands. They may advance our understanding of how tumors are rejected or, alternatively, tolerated by the immune system on the whole, and not just T or NK cells separately considered.
These observations strongly suggest that different tumors preferentially tamper with shared T/NK cell immunosuppressants and ligands, e.g. the two sides of the immunoevasion coin are indeed poor tumor lysis and poor lymphoid infiltration, as argued by Pietra et al. and Sconocchia et al., but these immunoevasive strategies directly impact on both T and NK cells.
In the case of HLA-E:NKG2A, a favorable outcome of an inhibitory interaction may appear paradoxical, but this apparent paradox can be alleviated by considering, among other factors taken into account in the original publication, that NK cells cannot be simply switched on and off, but need rheostat-like tuning. Unlicensed by default, they must undergo some kind of inhibitory receptor engagement prior to arming. Thus, HLA-E expression, if too low, might itself promote tumor escape.
Whatever the instructive role of self HLA-E, one may predict that harnessing a selected group of critical immune checkpoints will simultaneously unleash a range of immune effectors against cancer cells. Indeed, interference with a single function (antigen trimming in the endoplasmic reticulum) of tumor cells induces a subtle conformational change in MHC-I ligands that activates both T and NK cells, leading to the concerted rejection of a murine transplantable lymphoma that is otherwise refractory to immune elimination. Interestingly, the mechanism of action involves triggering and relief of inhibition, in T and NK cells respectively, by a single ligand (Figure 2C). This model is particularly relevant to the present issue, since tumor-rejecting T and NK cells are both highly lytic, and rapidly (within a few hours) convene at the tumor site (; Figure 2D and E).
Ongoing clinical trials with IDO inhibitors 1
Herlev Hospital, Copenhagen, Denmark
Incyte Corporation, Wilmington, DE
Herlev Hospital, Copenhagen, Denmark
Various solid tumors
Vanderbilt University, Nashville, TN and New Link Genetics Corporation, Ames, IA
Various solid tumors
Lee Moffit Cancer Center, Tampa, FL and Virginia Commonwealth University, Richmond, VA.
Various locations, Incyte Corporation, Wilmington, DE
Various solid tumors
Incyte Corporation, Wilmington, DE
In conclusion, the quality of the immune infiltrate (including the in situ interplay of immune ligands and their receptors, particularly those shared by T and NK cells) is in our opinion far more important than the absolute NK cell count in the tumor. Appropriate immunotherapeutic tactics are needed to overcome at the same time poor gathering and poor killing. And this applies to effectors of both the innate and the adaptive immunity.
Supported by AIRC IG grants (DF and PG) and 5 x 1000 (FL).
- Pietra G, Manzini C, Rivara S, Vitale M, Cantoni C, Petretto A, Balsamo M, Conte R, Benelli R, Minghelli S, Solari N, Gualco M, Queirolo P, Moretta L, Mingari MC: Melanoma cells inhibit natural killer cell function by modulating the expression of activating receptors and cytolytic activity. Cancer Res. 2012, 72: 1407-1415. 10.1158/0008-5472.CAN-11-2544.View ArticlePubMedGoogle Scholar
- Sconocchia G, Arriga R, Tornillo L, Terracciano L, Ferrone S, Spagnoli GC: Melanoma cells inhibit NK cell functions–letter. Cancer Res. 2012, 72: 5428-5429. 10.1158/0008-5472.CAN-12-1181.View ArticlePubMedGoogle Scholar
- Pietra G, Vitale M, Manzini C, Balsamo M, Moretta L, Mingari MC: Melanoma cells inhibit NK cell functions–response. Cancer Res. 2012, 72: 5430-10.1158/0008-5472.CAN-12-2526.View ArticleGoogle Scholar
- Shanker A, Marincola FM: Cooperativity of adaptive and innate immunity: implications for cancer therapy. Cancer Immunol Immunother. 2011, 60: 1061-1074. 10.1007/s00262-011-1053-z.PubMed CentralView ArticlePubMedGoogle Scholar
- Shanker A, Verdeil G, Buferne M, Inderberg-Suso EM, Puthier D, Joly F, Nguyen C, Leserman L, Auphan-Anezin N, Schmitt-Verhulst AM: CD8 T cell help for innate antitumor immunity. J Immunol. 2007, 179: 6651-6662.View ArticlePubMedGoogle Scholar
- Shanker A, Buferne M, Schmitt-Verhulst AM: Cooperative action of CD8 T lymphocytes and natural killer cells controls tumour growth under conditions of restricted T-cell receptor diversity. Immunology. 2010, 129: 41-54. 10.1111/j.1365-2567.2009.03150.x.PubMed CentralView ArticlePubMedGoogle Scholar
- Fruci D, Benevolo M, Cifaldi L, Lorenzi S, Lo Monaco E, Tremante E, Giacomini P: Major histocompatibility complex class I and tumour immuno-evasion: how to fool T cells and natural killer cells at one time. Curr Oncol. 2012, 19: 39-41.PubMed CentralView ArticlePubMedGoogle Scholar
- Godin-Ethier J, Hanafi LA, Piccirillo CA, Lapointe R: Indoleamine 2,3-dioxygenase expression in human cancers: clinical and immunologic perspectives. Clin Cancer Res. 2011, 17: 6985-6991. 10.1158/1078-0432.CCR-11-1331.View ArticlePubMedGoogle Scholar
- Greenhough A, Smartt HJ, Moore AE, Roberts HR, Williams AC, Paraskeva C, Kaidi A: The COX-2/PGE2 pathway: key roles in the hallmarks of cancer and adaptation to the tumour microenvironment. Carcinogenesis. 2009, 30: 377-386. 10.1093/carcin/bgp014.View ArticlePubMedGoogle Scholar
- Mandapathil M, Whiteside TL: Targeting human inducible regulatory T cells (Tr1) in patients with cancer: blocking of adenosine-prostaglandin E(2) cooperation. Expert Opin Biol Ther. 2011, 11: 1203-1214. 10.1517/14712598.2011.581225.PubMed CentralView ArticlePubMedGoogle Scholar
- Kalinski P: Regulation of immune responses by prostaglandin E2. J Immunol. 2012, 188: 21-28. 10.4049/jimmunol.1101029.PubMed CentralView ArticlePubMedGoogle Scholar
- Frumento G, Rotondo R, Tonetti M, Damonte G, Benatti U, Ferrara GB: Tryptophan-derived Catabolites Are Responsible for Inhibition of T and Natural Killer Cell Proliferation Induced by Indoleamine 2,3-Dioxygenase. J Exp Med. 2002, 196: 459-468. 10.1084/jem.20020121.PubMed CentralView ArticlePubMedGoogle Scholar
- Brandacher G, Perathoner A, Ladurner R, Schneeberger S, Obrist P, Winkler C, Werner ER, Werner-Felmayer G, Weiss HG, Gobel G, Margreiter R, Konigsrainer A, Fuchs D, Amberger A: Prognostic value of indoleamine 2,3-dioxygenase expression in colorectal cancer: effect on tumor-infiltrating T cells. Clin Cancer Res. 2006, 12: 1144-1151. 10.1158/1078-0432.CCR-05-1966.View ArticlePubMedGoogle Scholar
- Gao YF, Peng RQ, Li J, Ding Y, Zhang X, Wu XJ, Pan ZZ, Wan DS, Zeng YX, Zhang XS: The paradoxical patterns of expression of indoleamine 2,3-dioxygenase in colon cancer. J Transl Med. 2009, 7: 71-10.1186/1479-5876-7-71.PubMed CentralView ArticlePubMedGoogle Scholar
- Lo Monaco E, Tremante E, Cerboni C, Melucci E, Sibilio L, Zingoni A, Nicotra MR, Natali PG, Giacomini P: Human Leukocyte Antigen E contributes to protect tumor cells from lysis by natural killer cells. Neoplasia. 2011, 13: 822-830.View ArticlePubMedGoogle Scholar
- Benevolo M, Mottolese M, Tremante E, Rollo F, Diodoro MG, Ercolani C, Sperduti I, Lo Monaco E, Cosimelli M, Giacomini P: High expression of HLA-E in colorectal carcinoma is associated with a favorable prognosis. J Transl Med. 2011, 9: 184-10.1186/1479-5876-9-184.PubMed CentralView ArticlePubMedGoogle Scholar
- Joncker NT, Fernandez NC, Treiner E, Vivier E, Raulet DH: NK cell responsiveness is tuned commensurate with the number of inhibitory receptors for self-MHC class I: the rheostat model. J Immunol. 2009, 182: 4572-4580. 10.4049/jimmunol.0803900.PubMed CentralView ArticlePubMedGoogle Scholar
- Kim S, Poursine-Laurent J, Truscott SM, Lybarger L, Song YJ, Yang L, French AR, Sunwoo JB, Lemieux S, Hansen TH, Yokoyama WM: Licensing of natural killer cells by host major histocompatibility complex class I molecules. Nature. 2005, 436: 709-713. 10.1038/nature03847.View ArticlePubMedGoogle Scholar
- Cifaldi L, Lo Monaco E, Forloni M, Giorda E, Lorenzi S, Petrini S, Tremante E, Pende D, Locatelli F, Giacomini P, Fruci D: Natural killer cells efficiently reject lymphoma silenced for the endoplasmic reticulum aminopeptidase associated with antigen processing. Cancer Res. 2011, 71: 1597-1606. 10.1158/0008-5472.CAN-10-3326.View ArticlePubMedGoogle Scholar
- Pilla L, Rivoltini L, Patuzzo R, Marrari A, Valdagni R, Parmiani G: Multipeptide vaccination in cancer patients. Expert Opin Biol Ther. 2009, 9: 1043-1055. 10.1517/14712590903085109.View ArticlePubMedGoogle Scholar
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