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Mechanisms of tumor-induced T cell immune suppression and therapeutics to counter those effects

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Abstract

The theory of tumor immune surveillance states that the host immune system has means to recognize transformed cells and kills them to prevent growth and spreading of those cells. Nevertheless, cancer cells often survive and outgrow to form a tumor mass and metastasize to other tissues or organs. During the stage of immune evasion of tumor, various changes takes place both in the tumor cells and the tumor microenvironment to divert the anti-tumor immune responses by T cells and natural killer cells. Advances in the basic science in tumor immunology have led to development of many creative strategies to overcome the immune suppression imposed during tumor progression, a few of which have been approved for the treatment of cancer patients in the clinic. In the first part of this review, mechanisms of tumor-induced T cell immune suppression resulting in immune evasion of tumors will be discussed. In the second part, emerging methods to harness the immune responses against tumors will be introduced.

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References

  • Ahmad, S.M., S.K. Larsen, I.M. Svane, and M.H. Andersen. 2014. Harnessing PD-L1-specific cytotoxic T cells for anti-leukemia immunotherapy to defeat mechanisms of immune escape mediated by the PD-1 pathway. Leukemia 28: 236–238.

    CAS  PubMed  Google Scholar 

  • Ahmadzadeh, M., L.A. Johnson, B. Heemskerk, J.R. Wunderlich, M.E. Dudley, D.E. White, and S.A. Rosenberg. 2009. Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood 114: 1537–1544.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Akhurst, R.J., and A. Hata. 2012. Targeting the TGFbeta signalling pathway in disease. Nature Reviews Drug Discovery 11: 790–811.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Antonioli, L., P. Pacher, E.S. Vizi, and G. Hasko. 2013. CD39 and CD73 in immunity and inflammation. Trends in Molecular Medicine 19: 355–367.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Baldwin, R.W. 1955. Immunity to methylcholanthrene-induced tumours in inbred rats following atrophy and regression of the implanted tumours. British Journal of Cancer 9: 652–657.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Banchereau, J., and R.M. Steinman. 1998. Dendritic cells and the control of immunity. Nature 392: 245–252.

    CAS  PubMed  Google Scholar 

  • Bauer, S., V. Groh, J. Wu, A. Steinle, J.H. Phillips, L.L. Lanier, and T. Spies. 1999. Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science (New York, N.Y.) 285: 727–729.

    CAS  Google Scholar 

  • Beavis, P.A., J. Stagg, P.K. Darcy, and M.J. Smyth. 2012. CD73: A potent suppressor of antitumor immune responses. Trends in Immunology 33: 231–237.

    CAS  PubMed  Google Scholar 

  • Benitez, R., D. Godelaine, M.A. Lopez-Nevot, F. Brasseur, P. Jimenez, M. Marchand, M.R. Oliva, and N. Van Baren. 1998. Mutations of the beta2-microglobulin gene result in a lack of HLA class I molecules on melanoma cells of two patients immunized with MAGE peptides. Tissue Antigens 52: 520–529.

    CAS  PubMed  Google Scholar 

  • Blackburn, S.D., H. Shin, W.N. Haining, T. Zou, C.J. Workman, A. Polley, M.R. Betts, and G.J. Freeman. 2009. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nature Immunology 10: 29–37.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Blank, C., I. Brown, A.C. Peterson, M. Spiotto, Y. Iwai, T. Honjo, and T.F. Gajewski. 2004. PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells. Cancer Research 64: 1140–1145.

    CAS  PubMed  Google Scholar 

  • Blankenstein, T., P.G. Coulie, E. Gilboa, and E.M. Jaffee. 2012. The determinants of tumour immunogenicity. Nature Reviews Cancer 12: 307–313.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Boone, B.A., and M.T. Lotze. 2014. Targeting damage-associated molecular pattern molecules (DAMPs) and DAMP receptors in melanoma. Methods in Molecular Biology (Clifton, N.J.) 1102: 537–552.

    CAS  Google Scholar 

  • Boyman, O., and J. Sprent. 2012. The role of interleukin-2 during homeostasis and activation of the immune system. Nature Reviews Immunology 12: 180–190.

    CAS  PubMed  Google Scholar 

  • Burnet, F.M. 1970. The concept of immunological surveillance. Progress in Experimental Tumor Research 13: 1–27.

    CAS  PubMed  Google Scholar 

  • Callahan, M.K., and J.D. Wolchok. 2013. At the bedside: CTLA-4- and PD-1-blocking antibodies in cancer immunotherapy. Journal of Leukocyte Biology 94: 41–53.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Caserta, S., J.G. Borger, and R. Zamoyska. 2012. Central and effector memory CD4 and CD8 T-cell responses to tumor-associated antigens. Critical Reviews in Immunology 32: 97–126.

    CAS  PubMed  Google Scholar 

  • Cazac, B.B., and J. Roes. 2000. TGF-beta receptor controls B cell responsiveness and induction of IgA in vivo. Immunity 13: 443–451.

    CAS  PubMed  Google Scholar 

  • Cerwenka, A., A.B.H. Bakker, T. Mcclanahan, J. Wagner, J. Wu, J.H. Phillips, and L.L. Lanier. 2000. Retinoic acid early inducible genes define a ligand family for the activating NKG2D receptor in mice. Immunity 12: 721–727.

    CAS  PubMed  Google Scholar 

  • Cheadle, E.J., V. Sheard, A.A. Hombach, M. Chmielewski, T. Riet, C. Berrevoets, E. Schooten, C. Lamers, H. Abken, R. Debets, and D.E. Gilham. 2012. Chimeric antigen receptors for T-cell based therapy. Methods in Molecular Biology (Clifton, N.J.) 907: 645–666.

    CAS  Google Scholar 

  • Clynes, R.A., T.L. Towers, L.G. Presta, and J.V. Ravetch. 2000. Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nature Medicine 6: 443–446.

    CAS  PubMed  Google Scholar 

  • Corzo, C.A., M.J. Cotter, P. Cheng, F. Cheng, S. Kusmartsev, E. Sotomayor, T. Padhya, J.C. Mccaffrey, and D. Gabrilovich. 2009. Mechanism regulating reactive oxygen species in tumor-induced myeloid-derived suppressor cells. Journal of Immunology (Baltimore, Md.: 1950) 182: 5693–5701.

    CAS  Google Scholar 

  • Cosman, D., J. Mullberg, C.L. Sutherland, W. Chin, and R. Armitage. 2001. ULBPs, novel MHC class I-related molecules, bind to CMV glycoprotein UL16 and stimulate NK cytotoxicity through the NKG2D receptor. Immunity 14: 123–133.

    CAS  PubMed  Google Scholar 

  • Curiel, T.J., G. Coukos, L. Zou, X. Alvarez, P. Cheng, P. Mottram, M. Evdemon-Hogan, J.R. Conejo-Garcia, L. Zhang, and M. Burow. 2004. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nature Medicine 10: 942–949.

    CAS  PubMed  Google Scholar 

  • Darcy, P.K., P. Neeson, C.S. Yong, and M.H. Kershaw. 2014. Manipulating immune cells for adoptive immunotherapy of cancer. Current Opinion in Immunology 27: 46–52.

    CAS  PubMed  Google Scholar 

  • De Santo, C., P. Serafini, I. Marigo, L. Dolcetti, M. Bolla, P. Del Soldato, C. Melani, C. Guiducci, and M.P. Colombo. 2005. Nitroaspirin corrects immune dysfunction in tumor-bearing hosts and promotes tumor eradication by cancer vaccination. Proceedings of the National Academy of Sciences of the United States of America 102: 4185–4190.

    PubMed Central  PubMed  Google Scholar 

  • Dennis, K.L., N.R. Blatner, F. Gounari, and K. Khazaie. 2013. Current status of interleukin-10 and regulatory T-cells in cancer. Current Opinion in Oncology 25: 637–645.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Derynck, R. 2008. The TGF-β family, vol. 50. Cold Spring Harbor: Cold Spring Harbor Press.

    Google Scholar 

  • Derynck, R., and R.J. Akhurst. 2007. Differentiation plasticity regulated by TGF-[beta] family proteins in development and disease. Nature Cell Biology 9: 1000–1004.

    CAS  PubMed  Google Scholar 

  • Derynck, R., and Y.E. Zhang. 2003. Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 425: 577–584.

    CAS  PubMed  Google Scholar 

  • Diaz-Montero, C.M., J. Finke, and A.J. Montero. 2014. Myeloid-derived suppressor cells in cancer: Therapeutic, predictive, and prognostic implications. Seminars in Oncology 41: 174–184.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Dolcetti, L., E. Peranzoni, S. Ugel, I. Marigo, A. Fernandez Gomez, C. Mesa, M. Geilich, G. Winkels, E. Traggiai, A. Casati, F. Grassi, and V. Bronte. 2010. Hierarchy of immunosuppressive strength among myeloid-derived suppressor cell subsets is determined by GM-CSF. European Journal of Immunology 40: 22–35.

    CAS  PubMed  Google Scholar 

  • Dong, H., G. Zhu, K. Tamada, and L. Chen. 1999. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nature Medicine 5: 1365–1369.

    CAS  PubMed  Google Scholar 

  • Dunn, G.P., L.J. Old, and R.D. Schreiber. 2004. The three Es of cancer immunoediting. Annual Review of Immunology 22: 329–360.

    CAS  PubMed  Google Scholar 

  • Duttagupta, P.A., A.C. Boesteanu, and P.D. Katsikis. 2009. Costimulation signals for memory CD8+ T cells during viral infections. Critical Reviews in Immunology 29: 469–486.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Elia, A.R., P. Cappello, M. Puppo, T. Fraone, C. Vanni, A. Eva, T. Musso, F. Novelli, L. Varesio, and M. Giovarelli. 2008. Human dendritic cells differentiated in hypoxia down-modulate antigen uptake and change their chemokine expression profile. Journal of Leukocyte Biology 84: 1472–1482.

    CAS  PubMed  Google Scholar 

  • Eshhar, Z., T. Waks, and G. Grosst. 1992. Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the y or C subunits of the immunoglobulin and T-cell receptors. Proceedings of the National Academy of Sciences of the United States of America 90: 720–724.

    Google Scholar 

  • FDA. 2011. FDA approves Zelboraf and companion diagnostic test for late-stage skin cancer. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm268241.htm.

  • Fields, S.Z., S. Parshad, M. Anne, H. Raftopoulos, M.J. Alexander, M.L. Sherman, A. Laadem, V. Sung, and E. Terpos. 2013. Activin receptor antagonists for cancer-related anemia and bone disease. Expert Opinion on Investigational Drugs 22: 87–101.

    CAS  PubMed  Google Scholar 

  • Fife, B.T., K.E. Pauken, T.N. Eagar, T. Obu, J. Wu, Q. Tang, M. Azuma, M.F. Krummel, and J.A. Bluestone. 2009. Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal. Nature Immunology 10: 1185–1192.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Foley, E.J. 1953. Antigenic properties of methylcholanthrene-induced tumors in mice of the strain of origin. Cancer Research 13: 835–837.

    CAS  PubMed  Google Scholar 

  • Fourcade, J., Z. Sun, M. Benallaoua, P. Guillaume, I.F. Luescher, C. Sander, J.M. Kirkwood, V. Kuchroo, and H.M. Zarour. 2010. Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients. The Journal of Experimental Medicine 207: 2175–2186.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Francisco, L.M., V.H. Salinas, K.E. Brown, V.K. Vanguri, G.J. Freeman, V. Kuchroo, and A.H. Sharpe. 2009. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. The Journal of Experimental Medicine 206: 3015–3029.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Fredholm, B.B., A.P. Ijzerman, K.A. Jacobson, J. Linden, C.E. Muller, and International Union of Basic and Clinical Pharmacology. LXXXI. 2011. Nomenclature and classification of adenosine receptors—An update. Pharmacological Reviews 63: 1–34.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Freeman, G.J., A.J. Long, Y. Iwai, K. Bourque, T. Chernova, and H. Nishimura. 2000. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. The Journal of Experimental Medicine 192: 1027–1034.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Fridman, W.H., F. Pagès, C. Sautès-Fridman, and J. Galon. 2012. The immune contexture in human tumours: Impact on clinical outcome. Nature Reviews Cancer 12: 298–306.

    CAS  PubMed  Google Scholar 

  • Frumento, G., T. Piazza, E. Di Carlo, and S. Ferrini. 2006. Targeting tumor-related immunosuppression for cancer immunotherapy. Endocrine, Metabolic and Immune Disorders: Drug Targets 6: 233–237.

    Google Scholar 

  • Fujigaki, H., K. Saito, F. Lin, S. Fujigaki, K. Takahashi, B.M. Martin, C.Y. Chen, J. Masuda, J. Kowalak, O. Takikawa, M. Seishima, and S.P. Markey. 2006. Nitration and inactivation of IDO by peroxynitrite. Journal of immunology (Baltimore, Md.: 1950) 176: 372–379.

    CAS  Google Scholar 

  • Gabrilovich, D. 2004. Mechanisms and functional significance of tumour-induced dendritic-cell defects. Nature Reviews Immunology 4: 941–952.

    CAS  PubMed  Google Scholar 

  • Gabrilovich, D.I., V. Bronte, S.H. Chen, M.P. Colombo, A. Ochoa, S. Ostrand-Rosenberg, and H. Schneider. 2007. The terminology issue for myeloid-derived suppressor cells. Cancer Research 67: 425; author reply 426.

  • Gabrilovich, D.I., S. Ostrand-Rosenberg, and V. Bronte. 2012. Coordinated regulation of myeloid cells by tumours. Nature Reviews Immunology 12: 253–268.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Gajewski, T.F. 2012. Cancer immunotherapy. Molecular Oncology 6: 242–250.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Gaspari, P., T. Banerjee, W.P. Malachowski, A.J. Muller, G.C. Prendergast, J. Duhadaway, S. Bennett, and A.M. Donovan. 2006. Structure–activity study of brassinin derivatives as indoleamine 2,3-dioxygenase inhibitors. Journal of Medicinal Chemistry 49: 684–692.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ghebeh, H., S. Mohammed, A. Al-Omair, A. Qattan, C. Lehe, N. Elkum, M. Alshabanah, S. Bin Amer, A. Tulbah, and D. Ajarim. 2006. The B7-H1 (PD-L1) T lymphocyte-inhibitory molecule is expressed in breast cancer patients with infiltrating ductal carcinoma: Correlation with important high-risk prognostic factors. Neoplasia (New York, N.Y.) 8: 190–198.

    CAS  Google Scholar 

  • Ghiringhelli, F., C. Menard, M. Terme, C. Flament, J. Taieb, N. Chaput, P.E. Puig, S. Novault, B. Escudier, E. Vivier, A. Lecesne, and C. Robert. 2005. CD4+ CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor-beta-dependent manner. The Journal of Experimental Medicine 202: 1075–1085.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Giraldo, N.A., E. Becht, R. Remark, D. Damotte, C. Sautes-Fridman, and W.H. Fridman. 2014. The immune contexture of primary and metastatic human tumours. Current Opinion in Immunology 27: 8–15.

    CAS  PubMed  Google Scholar 

  • Goldman, B., and L. Defrancesco. 2009. The cancer vaccine roller coaster. Nature Biotechnology 27: 129–139.

    CAS  PubMed  Google Scholar 

  • Gromme, M., and J. Neefjes. 2002. Antigen degradation or presentation by MHC class I molecules via classical and non-classical pathways. Molecular Immunology 39: 181–202.

    CAS  PubMed  Google Scholar 

  • Gross, L. 1943. Intradermal Immunization of C3H Mice against a Sarcoma that originated in an animal of the same line. Cancer Research 3: 326–333.

    Google Scholar 

  • Grosso, J.F., and M.N. Jure-Kunkel. 2013. CTLA-4 blockade in tumor models: An overview of preclinical and translational research. Cancer Immunity 13: 5.

    PubMed Central  PubMed  Google Scholar 

  • Guerder, S., N. Joncker, K. Mahiddine, and L. Serre. 2013. Dendritic cells in tolerance and autoimmune diabetes. Current Opinion in Immunology 25: 670–675.

    CAS  PubMed  Google Scholar 

  • Hall, B.M., N.D. Verma, G.T. Tran, and S.J. Hodgkinson. 2011. Distinct regulatory CD4+ T cell subsets; differences between naive and antigen specific T regulatory cells. Current Opinion in Immunology 23: 641–647.

    CAS  PubMed  Google Scholar 

  • Hanson, E.M., V.K. Clements, P. Sinha, D. Ilkovitch, and S. Ostrand-Rosenberg. 2009. Myeloid-derived suppressor cells down-regulate l-selectin expression on CD4+ and CD8+. Journal of Immunology (Baltimore, Md.: 1950) 183: 937–944.

    CAS  Google Scholar 

  • Harding, C.V., and W.H. Boom. 2010. Regulation of antigen presentation by Mycobacterium tuberculosis: A role for Toll-like receptors. Nature Reviews Microbiology 8: 296–307.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Heine, P., N. Braun, L. Sevigny, S.C. Robson, J. Servos, and H. Zimmermann. 2001. The C-terminal cysteine-rich region dictates specific catalytic properties in chimeras of the ectonucleotidases NTPDase1 and NTPDase2. European Journal of Biochemistry/FEBS 268: 364–373.

    CAS  PubMed  Google Scholar 

  • Heitger, A. 2011. Regulation of expression and function of IDO in human dendritic cells. Current Medicinal Chemistry 18: 2222–2233.

    CAS  PubMed  Google Scholar 

  • Heldin, C.H., K. Miyazono, and P. Ten Dijke. 1997. TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature 390: 465–471.

    CAS  PubMed  Google Scholar 

  • Heuts, D.P., M.J. Weissenborn, R.V. Olkhov, A.M. Shaw, J. Gummadova, C. Levy, and N.S. Scrutton. 2012. Crystal structure of a soluble form of human CD73 with ecto-5′-nucleotidase activity. ChemBioChem: A European Journal of Chemical Biology 13: 2384–2391.

    CAS  PubMed  Google Scholar 

  • Hino, R., K. Kabashima, Y. Kato, H. Yagi, M. Nakamura, T. Honjo, T. Okazaki, and Y. Tokura. 2010. Tumor cell expression of programmed cell death-1 ligand 1 is a prognostic factor for malignant melanoma. Cancer 116: 1757–1766.

    PubMed  Google Scholar 

  • Hodi, F.S., S.J. O’day, D.F. Mcdermott, R.W. Weber, J.A. Sosman, J.B. Haanen, R. Gonzalez, C. Robert, D. Schadendorf, J.C. Hassel, W. Akerley, A.J.M. Van Den Eertwegh, J. Lutzky, P. Lorigan, J.M. Vaubel, G.P. Linette, D. Hogg, C.H. Ottensmeier, C. Lebbé, C. Peschel, I. Quirt, J.I. Clark, J.D. Wolchok, J.S. Weber, J. Tian, M.J. Yellin, G.M. Nichol, A. Hoos, and W.J. Urba. 2010. Improved survival with ipilimumab in patients with metastatic melanoma. New England Journal of Medicine 363: 711–723.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hoechst, B., J. Gamrekelashvili, M.P. Manns, T.F. Greten, and F. Korangy. 2011. Plasticity of human Th17 cells and iTregs is orchestrated by different subsets of myeloid cells. Blood 117: 6532–6541.

    CAS  PubMed  Google Scholar 

  • Huang, B., P.Y. Pan, Q. Li, A.I. Sato, D.E. Levy, J. Bromberg, C.M. Divino, and S.H. Chen. 2006. Gr-1 + CD115+ immature myeloid suppressor cells mediate the development of tumor-induced T regulatory cells and T-cell anergy in tumor-bearing host. Cancer Research 66: 1123–1131.

    CAS  PubMed  Google Scholar 

  • Hurwitz, A.A., and S.K. Watkins. 2012. Immune suppression in the tumor microenvironment: A role for dendritic cell-mediated tolerization of T cells. Cancer Immunology, Immunotherapy 61: 289–293.

    PubMed  Google Scholar 

  • Iwai, Y., M. Ishida, Y. Tanaka, T. Okazaki, T. Honjo, and N. Minato. 2002. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proceedings of the National Academy of Sciences of the United States of America 99: 12293–12297.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Jacobson, N.G., S.J. Szabo, R.M. Weber-Nordt, and Z. Zhong. 1995. Interleukin 12 signaling in T helper type 1 (Th1) cells involves tyrosine phosphorylation of signal transducer and activator of transcription (Stat)3 and Stat4. The Journal of Experimental Medicine 181: 1755–1762.

    CAS  PubMed  Google Scholar 

  • Jiang, Z.H., and R.R. Koganty. 2003. Synthetic vaccines: The role of adjuvants in immune targeting. Current Medicinal Chemistry 10: 1423–1439.

    CAS  PubMed  Google Scholar 

  • Jung, I.D., M.G. Lee, J.H. Chang, J.S. Lee, Y.I. Jeong, C.M. Lee, W.S. Park, J. Han, S.K. Seo, S.Y. Lee, and Y.M. Park. 2009. Blockade of indoleamine 2,3-dioxygenase protects mice against lipopolysaccharide-induced endotoxin shock. Journal of immunology (Baltimore, Md.: 1950) 182: 3146–3154.

    CAS  Google Scholar 

  • Kaisho, T., and S. Akira. 2002. Toll-like receptors as adjuvant receptors. Biochimica et Biophysica Acta 1589: 1–13.

    CAS  PubMed  Google Scholar 

  • Keir, M.E., M.J. Butte, G.J. Freeman, and A.H. Sharpe. 2008. PD-1 and its ligands in tolerance and immunity. Annual Review of Immunology 26: 677–704.

    CAS  PubMed  Google Scholar 

  • Khaled, Y.S., B.J. Ammori, and E. Elkord. 2013. Myeloid-derived suppressor cells in cancer: Recent progress and prospects. Immunology and Cell Biology 91: 493–502.

    CAS  PubMed  Google Scholar 

  • Kiessling, A., R. Wehner, S. Füssel, M. Bachmann, M.P. Wirth, and M. Schmitz. 2012. Tumor-associated antigens for specific immunotherapy of prostate cancer. Cancers 4: 193–217.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Koch, M.A., G. Tucker-Heard, N.R. Perdue, J.R. Killebrew, K.B. Urdahl, and D.J. Campbell. 2009. The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nature Immunology 10: 595–602.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kohrt, H.E., R. Houot, A. Marabelle, H.J. Cho, K. Osman, B. Goldman, C. Levy, and J. Brody. 2012. Combination strategies to enhance antitumor ADCC. Immunotherapy 4: 511–527.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kudrin, A. 2012. Overview of cancer vaccines: Considerations for development. Human Vaccines and Immunotherapeutics 8: 1335–1353.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kumar, S., W.P. Malachowski, J.B. Duhadaway, J.M. Lalonde, P.J. Carroll, D. Jaller, R. Metz, G.C. Prendergast, and A.J. Muller. 2008. Indoleamine 2,3-dioxygenase is the anticancer target for a novel series of potent naphthoquinone-based inhibitors. Journal of Medicinal Chemistry 51: 1706–1718.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kurts, C., H. Kosaka, F.R. Carbone, J.F. Miller, and W.R. Heath. 1997. Class I-restricted cross-presentation of exogenous self-antigens leads to deletion of autoreactive CD8(+) T cells. The Journal of Experimental Medicine 186: 239–245.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kusmartsev, S., and D.I. Gabrilovich. 2005. STAT1 signaling regulates tumor-associated macrophage-mediated T cell deletion. Journal of Immunology (Baltimore, Md.: 1950) 174: 4880–4891.

    CAS  Google Scholar 

  • Kwek, S.S., E. Cha, and L. Fong. 2012. Unmasking the immune recognition of prostate cancer with CTLA4 blockade. Nature Reviews Cancer 12: 289–297.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lanier, L.L., and J.H. Phillips. 1996. Inhibitory MHC class I receptors on NK cells and T cells. Immunology Today 17: 86–91.

    CAS  PubMed  Google Scholar 

  • Latchman, Y., C.R. Wood, T. Chernova, and D. Chaudhary. 2001. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nature Immunology 2: 261–268.

    CAS  PubMed  Google Scholar 

  • Lee, J.R., R.R. Dalton, J.L. Messina, M.D. Sharma, D.M. Smith, R.E. Burgess, F. Mazzella, S.J. Antonia, A.L. Mellor, and D.H. Munn. 2003. Pattern of recruitment of immunoregulatory antigen-presenting cells in malignant melanoma. Laboratory Investigation: A Journal of Technical Methods and Pathology 83: 1457–1466.

    CAS  Google Scholar 

  • Li, M.O., and R.A. Flavell. 2008. TGF-beta: A master of all T cell trades. Cell 134: 392–404.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Li, M.O., Y.Y. Wan, S. Sanjabi, A.K. Robertson, and R.A. Flavell. 2006a. Transforming growth factor-beta regulation of immune responses. Annual Review of Immunology 24: 99–146.

    CAS  PubMed  Google Scholar 

  • Li, W., K. Carper, Y. Liang, X.X. Zheng, C.S. Kuhr, J.D. Reyes, D.L. Perkins, A.W. Thomson, and J.D. Perkins. 2006b. Anti-CD25 mAb administration prevents spontaneous liver transplant tolerance. Transplantation Proceedings 38: 3207–3208.

    CAS  PubMed  Google Scholar 

  • Lichty, B.D., C.J. Breitbach, D.F. Stojdl, and J.C. Bell. 2014. Going viral with cancer immunotherapy. Nature Reviews Cancer 14: 559–567.

    CAS  PubMed  Google Scholar 

  • Lin, E.Y., J.F. Li, L. Gnatovskiy, Y. Deng, L. Zhu, D.A. Grzesik, H. Qian, X.N. Xue, and J.W. Pollard. 2006. Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer Research 66: 11238–11246.

    CAS  PubMed  Google Scholar 

  • Ling, W., J. Zhang, Z. Yuan, G. Ren, L. Zhang, X. Chen, A.B. Rabson, A.I. Roberts, Y. Wang, and Y. Shi. 2014. Mesenchymal stem cells use IDO to regulate immunity in tumor microenvironment. Cancer Research 74: 1576–1587.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Linsley, P.S., J.L. Greene, W. Brady, and J. Bajorath. 1994. Human B7-1 (CD80) and B7-2 (CD86) bind with similar avidities but distinct kinetics to CD28 and CTLA-4 receptors. Immunity 1: 793–801.

    CAS  PubMed  Google Scholar 

  • Lipson, E.J., and C.G. Drake. 2011. Ipilimumab: An anti-CTLA-4 antibody for metastatic melanoma. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 17: 6958–6962.

    CAS  Google Scholar 

  • Liu, X., N. Shin, H.K. Koblish, G. Yang, Q. Wang, L. Leffet, M.J. Hansbury, B. Thomas, and M. Rupar. 2010. Selective inhibition of IDO1 effectively regulates mediators of antitumor immunity. Blood 115: 3520–3530.

    CAS  PubMed  Google Scholar 

  • Lob, S., A. Konigsrainer, H.G. Rammensee, G. Opelz, and P. Terness. 2009. Inhibitors of indoleamine-2,3-dioxygenase for cancer therapy: Can we see the wood for the trees? Nature Reviews Cancer 9: 445–452.

    PubMed  Google Scholar 

  • Ma, C., T. Kapanadze, J. Gamrekelashvili, M.P. Manns, F. Korangy, and T.F. Greten. 2012. Anti-Gr-1 antibody depletion fails to eliminate hepatic myeloid-derived suppressor cells in tumor-bearing mice. Journal of Leukocyte Biology 92: 1199–1206.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Maby-El Hajjami, H., P. Ame-Thomas, C. Pangault, O. Tribut, J. Devos, R. Jean, N. Bescher, C. Monvoisin, J. Dulong, T. Lamy, T. Fest, and K. Tarte. 2009. Functional alteration of the lymphoma stromal cell niche by the cytokine context: Role of indoleamine-2,3 dioxygenase. Cancer Research 69: 3228–3237.

    CAS  PubMed  Google Scholar 

  • Mackall, C.L., M.S. Merchant, and T.J. Fry. 2014. Immune-based therapies for childhood cancer. Nature Reviews Clinical Oncology 11: 693–703.

    CAS  PubMed  Google Scholar 

  • Maldonado, R.A., and U.H. Von Andrian. 2010. How tolerogenic dendritic cells induce regulatory T cells. Advances in Immunology 108: 111–165.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Mancino, A., T. Schioppa, P. Larghi, F. Pasqualini, M. Nebuloni, I.H. Chen, S. Sozzani, J.M. Austyn, A. Mantovani, and A. Sica. 2008. Divergent effects of hypoxia on dendritic cell functions. Blood 112: 3723–3734.

    CAS  PubMed  Google Scholar 

  • Mantovani, A., S. Sozzani, M. Locati, P. Allavena, and A. Sica. 2002. Macrophage polarization: Tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends in Immunology 23: 549–555.

    CAS  PubMed  Google Scholar 

  • Markowitz, J., R. Wesolowski, T. Papenfuss, T.R. Brooks, and W.E. Carson III. 2013. Myeloid-derived suppressor cells in breast cancer. Breast Cancer Research and Treatment 140: 13–21.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Maus, M.V., S.A. Grupp, D.L. Porter, and C.H. June. 2014. Antibody-modified T cells: CARs take the front seat for hematologic malignancies. Blood 123: 2625–2635.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Melief, C.J. 2008. Cancer immunotherapy by dendritic cells. Immunity 29: 372–383.

    CAS  PubMed  Google Scholar 

  • Mellor, A.L., and D.H. Munn. 2004. IDO expression by dendritic cells: Tolerance and tryptophan catabolism. Nature Reviews Immunology 4: 762–774.

    CAS  PubMed  Google Scholar 

  • Mellor, A.L., D.B. Keskin, T. Johnson, P. Chandler, and D.H. Munn. 2002. Cells expressing indoleamine 2,3-dioxygenase inhibit T cell responses. Journal of Immunology (Baltimore, Md.: 1950) 168: 3771–3776.

    CAS  Google Scholar 

  • Mellor, A.L., B. Baban, P.R. Chandler, A. Manlapat, D.J. Kahler, and D.H. Munn. 2005. Cutting edge: CpG oligonucleotides induce splenic CD19+ dendritic cells to acquire potent indoleamine 2,3-dioxygenase-dependent T cell regulatory functions via IFN Type 1 signaling. Journal of Immunology (Baltimore, Md.: 1950) 175: 5601–5605.

    CAS  Google Scholar 

  • Menard, C., J.Y. Blay, C. Borg, S. Michiels, F. Ghiringhelli, C. Robert, C. Nonn, N. Chaput, J. Taieb, N.F. Delahaye, C. Flament, J.F. Emile, A. Le Cesne, and L. Zitvogel. 2009. Natural killer cell IFN-gamma levels predict long-term survival with imatinib mesylate therapy in gastrointestinal stromal tumor-bearing patients. Cancer Research 69: 3563–3569.

    CAS  PubMed  Google Scholar 

  • Mescher, M.F., P. Agarwal, K.A. Casey, C.D. Hammerbeck, Z. Xiao, and J.M. Curtsinger. 2007. Molecular basis for checkpoints in the CD8 T cell response: Tolerance versus activation. Seminars in Immunology 19: 153–161.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Mitsuka, K., T. Kawataki, E. Satoh, T. Asahara, T. Horikoshi, and H. Kinouchi. 2013. Expression of indoleamine 2,3-dioxygenase and correlation with pathological malignancy in gliomas. Neurosurgery 72: 1031–1038; discussion 1038–1039.

  • Miyara, M., Y. Ito, and S. Sakaguchi. 2014. TREG-cell therapies for autoimmune rheumatic diseases. Nature Reviews Rheumatology 10: 543–551.

    CAS  PubMed  Google Scholar 

  • Morelli, A.E., and A.W. Thomson. 2007. Tolerogenic dendritic cells and the quest for transplant tolerance. Nature Reviews Immunology 7: 610–621.

    CAS  PubMed  Google Scholar 

  • Moretta, A., R. Biassoni, C. Bottino, and D. Pende. 1997. Major histocompatibility complex class I-specific receptors on human natural killer and T lymphocytes. Immunological Reviews 155: 105–117.

    CAS  PubMed  Google Scholar 

  • Mucida, D., and H. Cheroutre. 2010. The many face-lifts of CD4 T helper cells. Advances in Immunology 107: 139–152.

    CAS  PubMed  Google Scholar 

  • Muller, A.J., and P.A. Scherle. 2006. Targeting the mechanisms of tumoral immune tolerance with small-molecule inhibitors. Nature Reviews Cancer 6: 613–625.

    CAS  PubMed  Google Scholar 

  • Munn, D.H., M. Zhou, J.T. Attwood, I. Bondarev, S.J. Conway, B. Marshall, C. Brown, and A.L. Mellor. 1998. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science (New York, N.Y.) 281: 1191–1193.

    CAS  Google Scholar 

  • Munn, D.H., M.D. Sharma, B. Baban, H.P. Harding, Y. Zhang, D. Ron, and A.L. Mellor. 2005. GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. Immunity 22: 633–642.

    CAS  PubMed  Google Scholar 

  • NCT00617422. 1-Methyl-d-tryptophan in treating patients with metastatic or refractory solid tumors that cannot be removed by surgery.

  • Nishikawa, H., and S. Sakaguchi. 2014. Regulatory T cells in cancer immunotherapy. Current Opinion in Immunology 27: 1–7.

    CAS  PubMed  Google Scholar 

  • Novitskiy, S.V., S. Ryzhov, R. Zaynagetdinov, A.E. Goldstein, Y. Huang, O.Y. Tikhomirov, M.R. Blackburn, I. Biaggioni, D.P. Carbone, I. Feoktistov, and M.M. Dikov. 2008. Adenosine receptors in regulation of dendritic cell differentiation and function. Blood 112: 1822–1831.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Noy, R., and J.W. Pollard. 2014. Tumor-associated macrophages: From mechanisms to therapy. Immunity 41: 49–61.

    CAS  PubMed Central  PubMed  Google Scholar 

  • O’Brien, T.G., L.C. Megosh, G. Gilliard, and A.P. Soler. 1997. Ornithine decarboxylase overexpression is a sufficient condition for tumor promotion in mouse skin. Cancer Research 57: 2630–2637.

    PubMed  Google Scholar 

  • O’Garra, A., and P. Vieira. 2004. Regulatory T cells and mechanisms of immune system control. Nature Medicine 10: 801–805.

    PubMed  Google Scholar 

  • O’Sullivan, B., and R. Thomas. 2003. CD40 and dendritic cell function. Critical Reviews in Immunology 23: 83–107.

    PubMed  Google Scholar 

  • Oh, S.A., and M.O. Li. 2013. TGF-beta: Guardian of T cell function. Journal of Immunology (Baltimore, Md.: 1950) 191: 3973–3979.

    CAS  Google Scholar 

  • Ohigashi, Y., M. Sho, Y. Yamada, Y. Tsurui, K. Hamada, H. Ikeda, T. Mizuno, H. Kashizuka, K. Yane, F. Tsushima, N. Otsuki, M. Azuma, and Y. Nakajima. 2005. Clinical significance of programmed death-1 ligand-1 and programmed death-1 ligand-2 expression in human esophageal cancer. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 11: 2947–2953.

    CAS  Google Scholar 

  • Pan, P.Y., G. Ma, K.J. Weber, J. Ozao-Choy, G. Wang, B. Yin, C.M. Divino, and S.H. Chen. 2010. Immune stimulatory receptor CD40 is required for T-cell suppression and T regulatory cell activation mediated by myeloid-derived suppressor cells in cancer. Cancer Research 70: 99–108.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Pardali, E., and P. Ten Dijke. 2012. TGF-β signaling and cardiovascular diseases. International Journal of Biological Sciences 8: 195–213.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Pardoll, D. 2003. Does the immune system see tumors as foreign or self? Annual Review of Immunology 21: 807–839.

    CAS  PubMed  Google Scholar 

  • Pardoll, D.M. 2012. The blockade of immune checkpoints in cancer immunotherapy. Nature Reviews Cancer 12: 252–264.

    CAS  PubMed  Google Scholar 

  • Park, T.S., S.A. Rosenberg, and R.A. Morgan. 2011. Treating cancer with genetically engineered T cells. Trends in Biotechnology 29: 550–557.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Perez-Gracia, J.L., S. Labiano, M.E. Rodriguez-Ruiz, M.F. Sanmamed, and I. Melero. 2014. Orchestrating immune check-point blockade for cancer immunotherapy in combinations. Current Opinion in Immunology 27: 89–97.

    CAS  PubMed  Google Scholar 

  • Pickup, M., S. Novitskiy, and H.L. Moses. 2013. The roles of TGFbeta in the tumour microenvironment. Nature Reviews Cancer 13: 788–799.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Pillay, J., T. Tak, V.M. Kamp, and L. Koenderman. 2013. Immune suppression by neutrophils and granulocytic myeloid-derived suppressor cells: Similarities and differences. Cellular and Molecular Life Sciences 70: 3813–3827.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Platten, M., W. Wick, and B.J. Van Den Eynde. 2012. Tryptophan catabolism in cancer: Beyond IDO and tryptophan depletion. Cancer Research 72: 5435–5440.

    CAS  PubMed  Google Scholar 

  • Prehn, R.T., and J.M. Main. 1957. Immunity to methylcholanthrene-induced sarcomas. Journal of the National Cancer Institute 18: 769–778.

    CAS  PubMed  Google Scholar 

  • Quail, D.F., and J.A. Joyce. 2013. Microenvironmental regulation of tumor progression and metastasis. Nature Medicine 19: 1423–1437.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Raber, P., A.C. Ochoa, and P.C. Rodriguez. 2012. Metabolism of l-arginine by myeloid-derived suppressor cells in cancer: Mechanisms of T cell suppression and therapeutic perspectives. Immunological Investigations 41: 614–634.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Raimondi, G., M.S. Turner, A.W. Thomson, and P.A. Morel. 2007. Naturally occurring regulatory T cells: Recent insights in health and disease. Critical Reviews in Immunology 27: 61–95.

    CAS  PubMed  Google Scholar 

  • Rech, A.J., and R.H. Vonderheide. 2009. Clinical use of anti-CD25 antibody daclizumab to enhance immune responses to tumor antigen vaccination by targeting regulatory T cells. Annals of the New York Academy of Sciences 1174: 99–106.

    CAS  PubMed  Google Scholar 

  • Regateiro, F.S., D. Howie, K.F. Nolan, E.I. Agorogiannis, D.R. Greaves, S.P. Cobbold, and H. Waldmann. 2011. Generation of anti-inflammatory adenosine by leukocytes is regulated by TGF-beta. European Journal of Immunology 41: 2955–2965.

    CAS  PubMed  Google Scholar 

  • Ribatti, D. 2013. Mast cells and macrophages exert beneficial and detrimental effects on tumor progression and angiogenesis. Immunology Letters 152: 83–88.

    CAS  PubMed  Google Scholar 

  • Riley, J.L., M. Mao, S. Kobayashi, M. Biery, J. Burchard, G. Cavet, B.P. Gregson, C.H. June, and P.S. Linsley. 2002. Modulation of TCR-induced transcriptional profiles by ligation of CD28, ICOS, and CTLA-4 receptors. Proceedings of the National Academy of Sciences of the United States of America 99: 11790–11795.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Rodriguez, P.C., D.G. Quiceno, J. Zabaleta, B. Ortiz, A.H. Zea, M.B. Piazuelo, A. Delgado, P. Correa, J. Brayer, E.M. Sotomayor, S. Antonia, A. Ochoa, and J.B. Ochoa. 2004. Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses. Cancer Research 64: 5839–5849.

    CAS  PubMed  Google Scholar 

  • Rudd, C.E., A. Taylor, and H. Schneider. 2009. CD28 and CTLA-4 coreceptor expression and signal transduction. Immunological Reviews 229: 12–26.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sakuishi, K., L. Apetoh, J.M. Sullivan, B.R. Blazar, V.K. Kuchroo, and A.C. Anderson. 2010. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. The Journal of Experimental Medicine 207: 2187–2194.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sato, K., K. Ozaki, I. Oh, A. Meguro, K. Hatanaka, T. Nagai, K. Muroi, and K. Ozawa. 2007. Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells. Blood 109: 228–234.

    CAS  PubMed  Google Scholar 

  • Schneider, H., J. Downey, A. Smith, B.H. Zinselmeyer, C. Rush, J.M. Brewer, B. Wei, and N. Hogg. 2006. Reversal of the TCR stop signal by CTLA-4. Science (New York, N.Y.) 313: 1972–1975.

    CAS  Google Scholar 

  • Sharma, M.D., B. Baban, P. Chandler, D.Y. Hou, N. Singh, H. Yagita, M. Azuma, B.R. Blazar, A.L. Mellor, and D.H. Munn. 2007. Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase. The Journal of Clinical Investigation 117: 2570–2582.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sheen, Y.Y., M.J. Kim, S.A. Park, S.Y. Park, and J.S. Nam. 2013. Targeting the transforming growth factor-beta signaling in cancer therapy. Biomolecules and Therapeutics 21: 323–331.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Shevach, E.M. 2009. Mechanisms of foxp3+ T regulatory cell-mediated suppression. Immunity 30: 636–645.

    CAS  PubMed  Google Scholar 

  • Shi, Y., and J. Massagué. 2003. Mechanisms of TGF-β signaling from cell membrane to the nucleus. Cell 113: 685–700.

    CAS  PubMed  Google Scholar 

  • Simpson, A.J., O.L. Caballero, A. Jungbluth, Y.T. Chen, and L.J. Old. 2005. Cancer/testis antigens, gametogenesis and cancer. Nature Reviews Cancer 5: 615–625.

    CAS  PubMed  Google Scholar 

  • Simpson, T.R., F. Li, and W. Montalvo-Ortiz. 2013. Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. JEM 210: 1695–1710.

    CAS  Google Scholar 

  • Singh, H., H. Huls, P. Kebriaei, and L.J. Cooper. 2014. A new approach to gene therapy using Sleeping Beauty to genetically modify clinical-grade T cells to target CD19. Immunological Reviews 257: 181–190.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sperlagh, B., and E.S. Vizi. 2011. The role of extracellular adenosine in chemical neurotransmission in the hippocampus and Basal Ganglia: Pharmacological and clinical aspects. Current Topics in Medicinal Chemistry 11: 1034–1046.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Stagg, J., and M.J. Smyth. 2010. Extracellular adenosine triphosphate and adenosine in cancer. Oncogene 29: 5346–5358.

    CAS  PubMed  Google Scholar 

  • Stauss, H.J., and E.C. Morris. 2013. Immunotherapy with gene-modified T cells: Limiting side effects provides new challenges. Gene Therapy 20: 1029–1032.

    CAS  PubMed  Google Scholar 

  • Strater, N. 2006. Ecto-5′-nucleotidase: Structure function relationships. Purinergic Signalling 2: 343–350.

    PubMed Central  PubMed  Google Scholar 

  • Talmadge, J.E. 2007. Pathways mediating the expansion and immunosuppressive activity of myeloid-derived suppressor cells and their relevance to cancer therapy. Clinical Cancer Research 13: 5243–5248.

    CAS  PubMed  Google Scholar 

  • Thomas, A., and R. Hassan. 2012. Immunotherapies for non-small-cell lung cancer and mesothelioma. The Lancet Oncology 13: e301–e310.

    CAS  PubMed  Google Scholar 

  • Thompson, L.F., H.K. Eltzschig, J.C. Ibla, C.J. Van De Wiele, R. Resta, J.C. Morote-Garcia, and S.P. Colgan. 2004. Crucial role for ecto-5′-nucleotidase (CD73) in vascular leakage during hypoxia. The Journal of Experimental Medicine 200: 1395–1405.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Töpfer, K., S. Kempe, N. Müller, and M. Schmitz. 2011. Tumor evasion from T cell surveillance. Journal of Biomedicine and Biotechnology 2011: 19.

    Google Scholar 

  • Trapani, J.A., and M.J. Smyth. 2002. Functional significance of the perforin/granzyme cell death pathway. Nature 2: 735–747.

    CAS  Google Scholar 

  • Tseng, S.Y., M. Otsuji, K. Gorski, X. Huang, J.E. Slansky, S.I. Pai, A. Shalabi, T. Shin, D. Pardoll, and H. Tsuchiya. 2001. B7-DC, a new dendritic cell molecule with potent costimulatory properties for T cells. The Journal of Experimental Medicine 193: 839–846.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Uyttenhove, C., L. Pilotte, I. Theate, V. Stroobant, D. Colau, N. Parmentier, B. Van Den Eynde, and T. Boon. 2003. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nature Medicine 9: 1269–1274.

    CAS  PubMed  Google Scholar 

  • Van De Berg, P.J., E.M. Van Leeuwen, I.J. Ten Berge, and R. Van Lier. 2008. Cytotoxic human CD4(+) T cells. Current Opinion in Immunology 20: 339–343.

    PubMed  Google Scholar 

  • Van Der Merwe, P.A., D.L. Bodian, S. Daenke, P. Linsley, and S.J. Davis. 1997. CD80 (B7-1) binds both CD28 and CTLA-4 with a low affinity and very fast kinetics. The Journal of Experimental Medicine 185: 393–403.

    PubMed Central  PubMed  Google Scholar 

  • Vasievich, E.A., and L. Huang. 2011. The suppressive tumor microenvironment: A challenge in cancer immunotherapy. Molecular Pharmaceutics 8: 635–641.

    CAS  PubMed  Google Scholar 

  • Vatsan, R.S., P.F. Bross, K. Liu, M. Theoret, A.R. De Claro, J. Lu, W. Helms, B. Niland, S.R. Husain, and R.K. Puri. 2013. Regulation of immunotherapeutic products for cancer and FDA’s role in product development and clinical evaluation. Journal for Immunotherapy of Cancer 1: 5.

    PubMed Central  PubMed  Google Scholar 

  • Vigneron, N., V. Stroobant, B.J. Van Den Eynde, and P. Van Der Bruggen. 2013. Database of T cell-defined human tumor antigens: The 2013 update. Cancer Immunity 13: 15.

    PubMed Central  PubMed  Google Scholar 

  • Villadangos, J.A. 2001. Presentation of antigens by MHC class II molecules: Getting the most out of them. Molecular Immunology 38: 329–346.

    CAS  PubMed  Google Scholar 

  • Vivier, E., S. Ugolini, D. Blaise, C. Chabannon, and L. Brossay. 2012. Targeting natural killer cells and natural killer T cells in cancer. Nature Reviews Immunology 12: 239–252.

    CAS  PubMed  Google Scholar 

  • Von Andrian, U.H., and T.R. Mempel. 2003. Homing and cellular traffic in lymph nodes. Nature Reviews Immunology 3: 867–878.

    Google Scholar 

  • Wahl, S.M., J. Wen, and N. Moutsopoulos. 2006. TGF-beta: A mobile purveyor of immune privilege. Immunological Reviews 213: 213–227.

    CAS  PubMed  Google Scholar 

  • Wang, R.F. 2001. The role of MHC class II-restricted tumor antigens and CD4+ T cells in antitumor immunity. Trends in Immunology 22: 269–276.

    PubMed  Google Scholar 

  • Wang, J., T.G. Blanchard, and P.B. Ernst. 2001. Host inflammatory response to infection. In Helicobacter pylori: Physiology and genetics, ed. H.L.T. Mobley, G.L. Mendz, and S.L. Hazell. Washington, DC: ASM Press.

    Google Scholar 

  • Weber, J. 2008. Overcoming immunologic tolerance to melanoma: Targeting CTLA-4 with ipilimumab (MDX-010). The Oncologist 13(Suppl 4): 16–25.

    CAS  PubMed  Google Scholar 

  • Westwood, J.A., L.J. Berry, L.X. Wang, C.P. Duong, H.J. Pegram, P.K. Darcy, and M.H. Kershaw. 2010. Enhancing adoptive immunotherapy of cancer. Expert Opinion on Biological Therapy 10: 531–545.

    CAS  PubMed  Google Scholar 

  • Wing, K., T. Yamaguchi, and S. Sakaguchi. 2011. Cell-autonomous and -non-autonomous roles of CTLA-4 in immune regulation. Trends in Immunology 32: 428–433.

    CAS  PubMed  Google Scholar 

  • Wolf, A.M., D. Wolf, G. Gastl, E. Gunsilius, and B. Grubeck-Loebenstein. 2003. Increase of regulatory T cells in the peripheral blood of cancer patients. Clinical Cancer Research 9: 606–612.

    PubMed  Google Scholar 

  • Yamane, H., and W.E. Paul. 2012. Cytokines of the [gamma]c family control CD4+ T cell differentiation and function. Nature Immunology 13: 1037–1044.

    CAS  PubMed  Google Scholar 

  • Yang, M., C. Ma, S. Liu, Q. Shao, W. Gao, B. Song, J. Sun, Q. Xie, Y. Zhang, A. Feng, Y. Liu, W. Hu, and X. Qu. 2010. HIF-dependent induction of adenosine receptor A2b skews human dendritic cells to a Th2-stimulating phenotype under hypoxia. Immunology and Cell Biology 88: 165–171.

    CAS  PubMed  Google Scholar 

  • Yegutkin, G.G. 2008. Nucleotide- and nucleoside-converting ectoenzymes: Important modulators of purinergic signalling cascade. Biochimica et Biophysica Acta 1783: 673–694.

    CAS  PubMed  Google Scholar 

  • Yokosuka, T., M. Takamatsu, W. Kobayashi-Imanishi, A. Hashimoto-Tane, M. Azuma, and T. Saito. 2012. Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2. The Journal of Experimental Medicine 209: 1201–1217.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Yoon, J.H., S.M. Jung, S.H. Park, M. Kato, T. Yamashita, I.K. Lee, K. Sudo, S. Nakae, J.S. Han, O.H. Kim, B.C. Oh, T. Sumida, M. Kuroda, J.H. Ju, K.C. Jung, S.H. Park, D.K. Kim, and M. Mamura. 2013. Activin receptor-like kinase5 inhibition suppresses mouse melanoma by ubiquitin degradation of Smad4, thereby derepressing eomesodermin in cytotoxic T lymphocytes. EMBO Molecular Medicine 5: 1720–1739.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Youn, J.I., S. Nagaraj, M. Collazo, and D.I. Gabrilovich. 2008. Subsets of myeloid-derived suppressor cells in tumor-bearing mice. Journal of Immunology (Baltimore, Md.: 1950) 181: 5791–5802.

    CAS  Google Scholar 

  • Yu, Z., M.R. Theoret, C.E. Touloukian, and D.R. Surman. 2004. Poor immunogenicity of a self/tumor antigen derives from peptide–MHC-I instability and is independent of tolerance. Clinical Investigation 114: 551–559.

    CAS  Google Scholar 

  • Zea, A.H., P.C. Rodriguez, M.B. Atkins, C. Hernandez, S. Signoretti, J. Zabaleta, D. Mcdermott, D. Quiceno, A. Youmans, A. O’Neill, J. Mier, and A.C. Ochoa. 2005. Arginase-producing myeloid suppressor cells in renal cell carcinoma patients: A mechanism of tumor evasion. Cancer Research 65: 3044–3048.

    CAS  PubMed  Google Scholar 

  • Zhang, Y., S.A. Kang, T. Mukherjee, S. Bale, B.R. Crane, and S.E. Ealick. 2007. Crystal structure and mechanism of tryptophan 2,3-dioxygenase, a heme enzyme involved in tryptophan catabolism and in quinolinate biosynthesis. Biochemistry 46: 145–155.

    CAS  PubMed  Google Scholar 

  • Zhang, Y., D. Lv, H.-J. Kim, R.A. Kurt, W. Bu, Y. Li, and X. Ma. 2013. A novel role of hematopoietic CCL5 in promoting triple-negative mammary tumor progression by regulating generation of myeloid-derived suppressor cells. Cell Research 23: 394–408.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Zheng, Y., Z. Cai, S. Wang, X. Zhang, J. Qian, S. Hong, H. Li, M. Wang, J. Yang, and Q. Yi. 2009. Macrophages are an abundant component of myeloma microenvironment and protect myeloma cells from chemotherapy drug-induced apoptosis. Blood 114: 3625–3628.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Zhu, C., A.C. Anderson, A. Schubart, H. Xiong, J. Imitola, S.J. Khoury, and X.X. Zheng. 2005. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nature Immunology 6: 1245–1252.

    CAS  PubMed  Google Scholar 

  • Zhu, J., H. Yamane, and W.E. Paul. 2010. Differentiation of effector CD4 T cell populations (*). Annual Review of Immunology 28: 445–489.

    CAS  PubMed Central  PubMed  Google Scholar 

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This work was supported by Chungnam National University Grant (2013-1892) to Inkyu Hwang.

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Hwang, I., Nguyen, N. Mechanisms of tumor-induced T cell immune suppression and therapeutics to counter those effects. Arch. Pharm. Res. 38, 1415–1433 (2015). https://doi.org/10.1007/s12272-015-0566-y

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