Rohit SHARMA, Daizee TALUKDAR, Parth MALIK, Tapan Kumar MUKHERJEE

Failure of immunological cells to eradicate tumor and cancer cells: an overview

Inflammation can be broadly understood as a successive immune response of an organism's immune system towards nonnative or foreign antigens. This is a protective mechanism of the immune system, mediated by diverse immunological cells, to ensure homeostasis of an individual. Once activated, these immunological cells release a number of cytokines, chemokines, reactive oxygen species, reactive nitrogen species, histamines, prostaglandins, and other materials leading to inflammation. Tumor cells express altered proteins due to mutations of their genes, DNA modifications such as histone modification, DNA methylation, or other mechanisms of altered protein expression. The body's immunological cells actively recognize these altered proteins, now acting as tumor antigens, and eliminate the tumor cell; this is popularly known as tumor immunosurveillance. However, in unmanaged or inexorable circumstances, tumor cells escape from immunosurveillance mechanisms. This ultimately leads to the cascading events of cancer development and progression. T regulatory cells, tumor-associated macrophages, and myeloid-derived suppressor cells are pronounced cells involved in immunosuppression. These cells not only dodge the immune system's surveillance but also significantly increase the survival, proliferation, and metastasis rates of tumor cells. They hinder T cytotoxic activation by secreting inhibitory cytokines (which inhibit the antitumor activity of natural killer cells) along with dendritic cells and disrupt presentation of antigens, ultimately leading to cancer development. On their own, these cells have emerged as promising therapeutic targets in cancer immunotherapy. This review highlights some of the mechanisms by which these cells escape immunosurveillance and mediate immune suppression.

Anahtar Kelimeler:

Tumor, cancer, inflammation, immunosurveillance, escape, immunosuppression

Failure of immunological cells to eradicate tumor and cancer cells: an overview

Keywords:

Tumor, cancer, inflammation, immunosurveillance, escape, immunosuppression,

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Altomonte M, Gloghini A, Bertola G, Gasparollo A, Carbone A, Ferrone S, Maio M (1993). Differential expression of cell adhesion molecules CD54/CD11 and CD58/CD2 by human melanoma cells and functional role in their interaction with cytotoxic cells. Cancer Res 53: 3343–3348.
Amiot L, Onno M, Lamy T, Dauriac C, Le Prise PY, Fauchet R, Drenou B (1998). Loss of MHC molecules in B lymphomas is associated with an aggressive clinical course. Br J Haematol 100: 655–663.
Badoual C, Hans S, Rodriguez J, Peyrard S, Klein C, Agueznay NH, Mosseri V, Laccourreye O, Bruneval P, Fridman WH et al. (2006). Prognostic value of tumor-infiltrating CD4+ T-cell subpopulations in head and neck cancers. Clin Cancer Res 12: 465–472.
Balkwill F, Mantovani A (2001). Inflammation and cancer: back to Virchow. Lancet 357: 539–545.
Banchereau J, Steinman RM (1998). Dendritic cells and the control of immunity. Nature 392: 245–252.
Bandrés E, Merino J, Vázquez B, Inogés S, Moreno C, Subirá ML, Sánchez-Ibarrola A (2000). The increase of IFN-gamma production through aging correlates with the expanded CD8(+high) CD28(-) CD57(+) subpopulation. Clin Immunol 96: 230–235.
Bernstein H, Payne CM, Bernstein C, Garewal H, Dvorak K (2008). Cancer and aging as consequences of un-repaired DNA damage. In: Kimura H, Suzuki A, editors. New Research on DNA Damages. New York, NY, USA: Nova Science Publishers, pp. 1–47.
Biswas S, Mantovani A (2010). Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol 11: 889–896.
Blair GE, Cook GP (2008).Cancer and the immune system: an overview. Oncogene 27: 5868.
Borg C, Terme M, Taieb J, Menard C, Flament C, Robert C, Maruyama K, Wakasugi H, Angevin E, Thielemans K et al. (2004). Novel mode of action of c-kit tyrosine kinase inhibitors leading to NK cell-dependent antitumor effects. J Clin Invest 114: 379–388.
Brenchley JM, Karandikar NJ, Betts MR, Ambrozak DR, Hill BJ, Crotty LE, Casazza JP, Kuruppu J, Migueles SA, Connors M et al. (2003). Expression of CD57 defines replicative senescence and antigen-induced apoptotic death of CD8+ T cells. Blood 101: 2711–2720.
Bronte V, Serafini P, Mazzoni A, Segal DM, Zanovello P (2003). L-arginine metabolism in myeloid cells controls T-lymphocyte functions. Trends Immunol 24: 302–306.
Bronte V, Zanovello P (2005). Regulation of immune responses by L-arginine metabolism. Nat Rev Immunol 5: 641–654.
Buechele C, Baessler T, Wirths S, Schmohl JU, Schmiedel BJ, Salih HR (2012). Glucocorticoid-induced TNFR-related protein (GITR) ligand modulates cytokine release and NK cell reactivity in chronic lymphocytic leukemia (CLL). Leukemia 5: 991–1000.
Burnet FM (1957). Cancer: a biological approach. Br Med J 1: 779– 786.
Burnet FM (1970). Immunological Surveillance. Oxford, UK: Pergamon Press.
Castriconi R, Dondero A, Augugliaro R, Cantoni C, Carnemolla B, Sementa AR, Negri F, Conte R, Corrias MV, Moretta L et al. (2004). Identification of 4Ig-B7-H3 as a neuroblastoma- associated molecule that exerts a protective role from an NK cell-mediated lysis. P Natl Acad Sci USA 101: 12640–12645.
Challis GB, Stam HJ (1990). The spontaneous regression of cancer. A review of cases from 1900 to 1987. Acta Oncologica 29: 545–550.
Chaput N, Louafi S, Bardier A, Charlotte F, Vaillant JC, Ménégaux F, Rosenzwajg M, Lemoine F, Klatzmann D, Taieb J et al. (2009). Identification of CD8+CD25+FOXP3+ suppressive T cells in colorectal cancer tissue. Gut 58: 520–529.
Charles KA, Kulbe H, Soper R, Escorcio-Correia M, Lawrence T, Schultheis A, Chakravarty P, Thompson RG, Kollias G, Smyth JF et al. (2009). The tumor-promoting actions of TNF-alpha involve TNFR1 and IL-17 in ovarian cancer in mice and humans. J Clin Invest 119: 3011–3023.
Chaturvedi V, Collison LW, Guy CS, Workman CJ, Vignali DA (2011). Cutting edge: human regulatory T cells require IL-35 to mediate suppression and infectious tolerance. J Immunol 186: 6661–6666.
Chettibi S, Ferguson MWJ (1999). Wound repair: an overview. In: Gallin JI, Snyderman R, editors. Inflammation: Basic Principles and Clinical Correlates. 3rd ed. Philadelphia, PA, USA: Lippincott Williams & Wilkins, pp. 865–881.
Chow MT, Moller A, Smyth MJ (2012). Inflammation and immune surveillance in cancer. Semin Cancer Biol 22: 23–32.
Chretien AS, Le Roy A, Vey N, Prebet T, Blaise D, Fauriat C, Olive D(2014). Cancer-induced alterations of NK-mediated target recognition: current and investigational pharmacological strategies aiming at restoring NK-mediated anti-tumor activity. Front Immunol 5: 122.
Collison LW, Workman CJ, Kuo TT, Boyd K, Wang Y, Vignali KM, Cross R, Sehy D, Blumberg RS, Vignali DA (2007). The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 450: 566–569.
Corzo CA, Condamine T, Lu L, Cotter MJ, Youn JI, Cheng P, Cho HI, Celis E, Quiceno DG, Padhya T et al. (2010). HIF-1α regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J Exp Med 207: 2439– 2453.
Cosulich ME, Rubartelli A, Risso A, Cozzolino F, Bargellesi R (1987). Functional characterization of an antigen involved in an early step of T-cell activation. P Natl Acad Sci USA 84: 4205–4209.
Daurkin I, Eruslanov E, Stoffs T, Perrin GQ, Algood C, Gilbert SM, Rosser CJ, Su LM, Vieweg J, Kusmartsev S (2011). Tumor-associated macrophages mediate immunosuppression in the renal cancer microenvironment by activating the 15-lipoxygenase-2 pathway. Cancer Res 71: 6400–6409.
Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD (2002). Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 3: 991–998.
Dunn GP, Old LJ, Schreiber RD (2004). The immunobiology of cancer immunosurveillance and immunoediting. Immunity 21: 137–148.
Endharti AT, Rifa IM, Shi Z, Fukuoka Y, Nakahara Y, Kawamoto Y, Takeda K, Isobe K, Suzuki H (2005). Cutting edge: CD8+CD122+ regulatory T cells produce IL-10 to suppress IFN-gamma production and proliferation of CD8+ T cells. J Immunol 175: 7093–7097.
Esplugues E, Sancho D, Vega-Ramos J, Martínez C, Syrbe U, Hamann A, Engel P, Sanchez-Madrid F, Lauzurica P (2003). Enhanced antitumor immunity in mice deficient in CD69. J Exp Med 197: 1093–1106.
Filaci G, Fenoglio D, Fravega M, Ansaldo G, Borgonovo G, Traverso P, Villaggio B, Ferrera A, Kunkl A, Rizzi M et al. (2007). CD8+ CD28- T regulatory lymphocytes inhibiting T cell proliferative and cytotoxic functions infiltrate human cancers. J Immunol 179: 4323–334.
Filipazzi P, Valenti R, Huber V, Pilla L, Canese P, Iero M, Castelli C, Mariani L, Parmiani G, Rivoltini L (2007). Identification of a new subset of myeloid suppressor cells in peripheral blood of melanoma patients with modulation by a granulocyte- macrophage colony-stimulation factor-based antitumor vaccine. J Clin Oncol 25: 2546–2553.
Finn OJ (2008). Molecular origins of cancer. Cancer immunology. N Engl J Med 358: 2704–2715.
Fontenot JD, Gavin MA, Rudensky AY (2003). Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 4: 330–336.
Gabrilovich DI, Chen HL, Girgis KR, Cunningham HT, Meny GM, Nadaf S, Kavanaugh D, Carbone DP (1996). Production of vascular endothelial growth factor by human tumor inhibits the functional maturation of dendritic cells. Nature Med 2: 1096–1103.
Gabrilovich DI, Nagaraj S (2009). Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 9: 162– 174.
Gao X, Zhu Y, Li G, Huang H, Zhang G, Wang F, Sun J, Yang Q, Zhang X, Lu B (2012). TIM-3 expression characterizes regulatory T cells in tumor tissues and is associated with lung cancer progression. PLoS One 7: e30676.
Garcia-Lora A, Algarra I, Gaforio JJ, Ruiz-Cabello F, Garrido F (2001). Immunoselection by T lymphocytes generates repeated MHC class 1 deficient metastatic tumor variants. Int J Cancer 91: 109–119.
Ghiringhelli F, Ménard C, Terme M, Flament C, Taieb J, Chaput N, Puig PE, Novault S, Escudier B, Vivier E et al. (2005). CD4+CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor–dependent manner. J Exp Med 202: 1075–1085.
Gowda M, Godder K, Kmieciak M, Worschech A, Ascierto ML, Wang E, Marincola FM, Manjili MH (2011). Distinct signatures of the immune responses in low risk versus high risk neuroblastoma. J Transl Med 9: 170.
Han Y, Guo Q, Zhang M, Chen Z, Cao X (2009). CD69+ CD4+ CD25- T cells, a new subset of regulatory T cells, suppress T cell proliferation through membrane-bound TGF-B1. J Immunol 182: 111–120.
Hanahan D, Weinberg RA (2011). Hallmarks of cancer: the next generation. Cell 144: 646–674.
Hasegawa Y, Takanashi S, Kanehira Y, Tsushima T, Imai T, Okumura K (2001). Transforming growth factor-β1 level correlates with angiogenesis, tumor progression, and prognosis in patients with nonsmall cell lung carcinoma. Cancer 91: 964–971.
Hori S, Nomura T, Sakaguchi S (2003). Control of regulatory T cell development by the transcription factor Foxp3. Science 299: 1057–1061.
Hoskin DW, Butler JJ, Drapeau D, Haeryfar SM, Blay J (2002). Adenosine acts through an A3 receptor to prevent the induction of murine anti-CD3-activated killer T cells. Int J Cancer 99: 386–395.
Houghton AN (1994). Cancer antigens: immune recognition of self and altered self. J Exp Med 180: 1–4.
Houghton AN, Gold JS, Blachere NE (2001). Immunity against cancer: lessons learned from melanoma. Curr Opin Immunol 13: 134–140.
Inozume T, Hanada K, Wang QJ, Yang JC (2009). IL-17 secreted by tumor reactive T cells induces IL-8 release by human renal cancer cells. J Immunother 32: 109–117.
Itoh M, Takeshi T, Noriko S, Yuhshi K, Jun S, Fujio O, Shimon S (1999). Thymus and autoimmunity: production of CD25+CD4+ naturally anergic and suppressive T cells as a key function of the thymus in maintaining immunologic self- tolerance. J Immunol 162: 5317–5326.
Kaech SM, Wherry EJ, Ahmed R (2002). Effector and memory T-cell differentiation: implications for vaccine development. Nat Rev Immunol 2: 251–262.
Kapp LA, Kapp LM, McKenna KC (2004). γδ T cells play an essential role in several forms of tolerance. Immunol Res 29: 93–102.
Kim R, Emi M, Tanabe K (2007). Cancer immunoediting from immunosurveillance to immunoescape. Immunity 121: 1–14.
Kiniwa Y, Miyahara Y, Wang HY, Peng W, Peng G, Wheeler TM, Thompson TC, Old LJ, Wang RF (2007). CD8+ FOXP3+ regulatory T cells mediate immunosuppression in prostate cancer. Clin Cancer Res 13: 6947–6458.
Kong FM, Washington MK, Jirtle RL, Anscher MS (1996). Plasma transforming growth factor reflects disease status in patients with lung cancer after radiotherapy: a possible tumor marker. Lung Cancer 16: 47–59.
Konturek PC, Kania J, Konturek JW, Nikiforuk A, Konturek SJ, Hahn EG (2003). H. pylori infection, atrophic gastritis, cytokines, gastrin, COX-2, PPARγ and impaired apoptosis in gastric carcinogenesis. Med Sci Monit 9: SR53–66.
Kuang DM, Peng C, Zhao Q, Wu Y, Chen MS, Zheng L (2010). Activated monocytes in peritumoral stroma of hepatocellular carcinoma promote expansion of memory T helper 17 cells. Hepatology 51: 154–164.
Kusmartsev S, Nefedova Y, Yoder D, Gabrilovich DI (2004). Antigen- specific inhibition of CD8+ T cell response by immature myeloid cells in cancer is mediated by reactive oxygen species. J Immunol 172: 989–999.
Lee JC, Lee KM, Kim DW, Heo DS (2004). Elevated TGF-β1 secretion and down-modulation of NKG2D underlies impaired NK cytotoxicity in cancer patients. J Immunol 172: 7335–7340.
Lehmann F, Marchand M, Hainaut P, Pouillart P, Sastre X, Ikeda H, Boon T, Coulie PG (1995). Differences in the antigens recognized by cytolytic T cells on two successive metastasis of a melanoma patient are consistent with immune selection. Eur J Immunol 25: 340–347.
LiJ, Huang ZF, Xiong G, Mo HY, Qiu F, Mai HQ, Chen QY, He J, Chen S, Zheng LM et al. (2011). Distribution, characterization, and induction of CD8 + regulatory T cells and IL-17-producing CD8 + T cells in nasopharyngeal carcinoma. J Transl Med 9: 189.
Liang B, Workman C, Lee J, Chew C, Dale BM, Colonna L, Flore M, Li N, Schweighoffer E, Greenberg S et al. (2008). Regulatory T cells inhibit dendritic cells by lymphocyte activation gene-3 engagement of MHC class II. J Immunol 180: 5916–5926.
Lin Y, Wei C, Liu Y, Qiu Y, Liu C, Guo F (2013). Selective ablation of tumor-associated macrophages suppresses metastasis and angiogenesis. Cancer Sci 104: 1217–1225.
Link AA, Kino T, Worth JA, McGuire JL, Crane ML, Chrousos GP, Wilder RL, Elenkov IJ (2000). Ligand activation of the adenosine A2a receptors inhibits IL-12 production by human monocytes. J Immunol 164: 436–442.
Liu C, Sun C, Huang H, Janda K, Edgington T (2003). Overexpression of legumain in tumors is significant for invasion/metastasis and a candidate enzymatic target for prodrug therapy. Cancer Res 63: 2957–2964.
Long J, Zhang X, Wen M, Kong Q, Lv Z, An Y, Wei XQ (2013). IL-35 over-expression increases apoptosis sensitivity and suppresses cell growth in human cancer cells. Biochem Biophys Res Commun 430: 364–369.
Luo Y, Zhou H, Krueger J, Kaplan C, Lee SH, Dolman C, Markowitz D, Wu W, Liu C, Reisfeld RA et al. (2006). Targeting tumor- associated macrophages as a novel strategy against breast cancer. J Clin Invest 116: 2132–2141.
Ma C, Zhang Q, Ye J, Wang F, Zhang Y, Wevers E, Schwartz T, Hunborg P, Varvares MA, Hoft DF et al. (2012). Tumor-infiltrating γδ T lymphocytes predict clinical outcome in human breast cancer. J Immunol 189: 5029–5036.
Mandruzzato S, Solito S, Falisi E, Francescato S, Chiarion-Sileni V, Mocellin S, Zanon A, Rossi CR, Nitti D, Bronte V et al. (2009). IL4Ra+ myeloid-derived suppressor cell expansion in cancer patients. J Immunol 182: 6562–6568.
Merino J, Martınez-Gonzalez MA, Rubio M, Inoges S, Sanchez- Ibarrola A, Subira ML (1998). Progressive decrease of CD8high+ CD28+ CD57- cells with ageing. Clin Exp Immunol 112: 48–51.
Mills CD, Kincaid K, Alt JM, Heilman MJ, Hill AM (2000). M-1/M-2 macrophages and the Th1/Th2 paradigm. J Immunol 164: 6166–6173.
Mingari MC, Ponte M, Bertone S, Schiavetti F, Vitale C, Bellomo R, Moretta A, Moretta L (1998). HLA class I-specific inhibitory receptors in human T lymphocytes: interleukin 15-induced expression of CD94/NKG2A in superantigen- or alloantigen- activated CD8+ T cells. P Natl Acad Sci USA 95: 1172–1177.
Mirza N, Fishman M, Fricke I, Dunn M, Neuger AM, Frost TJ, Lush RM, Antonia S, Gabrilovich DI (2006). All-trans-retinoic acid improves differentiation of myeloid cells and immune response in cancer patients. Cancer Res 66: 9299–9307.
Molon B, Ugel S, Del Pozzo F, Soldani C, Zilio S, Avella D, De Palma A, Mauri P, Monegal A, Rescigno M et al. (2011). Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells. J Exp Med 208: 1949–1962.
Mueller MM, Fusenig NE (1999). Constitutive expression of G-CSF and GM-CSF in human skin carcinoma cells with functional consequence for tumor progression. Int J Cancer 83: 780–789.
Mueller MM, Herold-Mende CC, Riede D, Lange M, Steiner HH, Fusenig NE (1999). Autocrine growth regulation by granulocyte colony-stimulating factor and granulocyte macrophage colony-stimulating factor in human gliomas with tumor progression. Am J Pathol 155: 1557–1567.
Mundy-Bosse BL, Lesinski GB, Jaime-Ramirez AC, Benninger K, Khan M, Kuppusamy P, Guenterberg K, Kondadasula SV, Chaudhury AR, La Perle KM et al. (2011). Myeloid-derived suppressor cell inhibition of the IFN response in tumor- bearing mice. Cancer Res 71: 5101–5110.
Murthy RV, Arbman G, Gao J, Roodman GD, Sun XF (2005). Legumain expression in relation to clinicopathologic and biological variables in colorectal cancer. Clin Cancer Res 11: 2293–2299.
Nagaraj S, Schrum AG, Cho HI, Celis E, Gabrilovich DI (2010). Mechanism of T cell tolerance induced by myeloid-derived suppressor cells. J Immunol 184: 3106–3116.
Nakamura K, Kitani A, Strober W (2001). Cell contact-dependent immunosuppression by CD4+ CD25+ regulatory T cell is mediated by cell surface-bound transforming growth factor β. J Exp Med 194: 629–643.
Naor D (1979). Suppressor cells: permitters and promoters of malignancy? Adv Cancer Res 29: 45–125.
Narai S, Watanabe M, Hasegawa H, Nishibori H, Endo T, Kubota T, Kitajima M (2002). Significance of transforming growth factor as a new tumor marker for colorectal cancer. Int J Cancer 97: 508–511.
Okegawa T, Pong RC, Li Y, Hsieh JT (2004). The role of cell adhesion molecule in cancer progression and its application in cancer therapy. Acta Biochim Pol 51: 445–457.
Onishi Y, Fehervari Z, Yamaguchi T, Sakaguchi S (2008). Foxp3+ natural regulatory T cells preferentially form aggregates on dendritic cells in vitro and actively inhibit their maturation. P Natl Acad Sci USA 29: 10113–10118.
Pedroza-Gonzalez A, Verhoef C, Ijzermans JN, Peppelenbosch MP, Kwekkeboom J, Verheij J, Janssen HL, Sprengers D (2013). Activated tumor-infiltrating CD4+ regulatory T cells restrain antitumor immunity in patients with primary or metastatic liver cancer. Hepatology 57: 183–194.
Peng G, Guo Z, Kiniwa Y, Voo KS, Peng W, Fu T, Wang DY, Li Y, Wang HY, Wang RF (2005). Toll-like receptor 8 mediated-reversal of CD4+ regulatory T cell function. Science 309: 1380–1384.
Peng G, Wang HY, Peng W, Kiniwa Y, Kook HS, Wang RF (2007). Tumor-infiltrating γδ T cells suppress T and dendritic cell function via mechanisms controlled by a unique toll-like receptor signaling pathway. Immunity 27: 334–348.
Pennington DJ, Vermijlen D, Wise EL, Clarke SL, Tigelaar RE, Hayday AC (2005). The integration of conventional and unconventional T cells that characterizes cell-mediated responses. Adv Immunol 87: 27–59.
Petrausch U, Poehlein CH, Jensen SM, Twitty C, Thompson JA, Assmann I, Puri S, LaCelle MG, Moudgil T, Maston L et al. (2009). Cancer immunotherapy: the role regulatory T cells play and what can be done to overcome their inhibitory effects. Curr Mol Med 9: 673–682.
Piccirillo CA, Letterio JJ, Thornton AM, McHugh RS, Mamura M, Mizuhara H, Shevach EM (2002). CD4 (+) CD25 (+) regulatory T cells can mediate suppressor function in the absence of transforming growth factor β1 production and responsiveness. J Exp Med 196: 237–246.
Poschke I, Mougiakakos D, Hansson J, Masucci GV, Kiessling R (2010). Immature immunosuppressive CD14+HLA-DR–/low cells in melanoma patients are Stat3hi and overexpress CD80, CD83, and DC-sign. Cancer Res 70: 4335–4345.
Qian B, Pollard J (2010). Macrophage diversity enhances tumor progression and metastasis. Cell 141: 39–51.
Ramirez R, Carracedo J, Castedo M, Zamzami N, Kroemer G (1996). CD69-induced monocyte apoptosis involves multiple nonredundant signaling pathways. Cell Immunol 172: 192– 199.
Read S, Malmstrom V, Powrie F (2000). Cytotoxic T lymphocyte- associated antigen 4 plays an essential role in the function of CD25 (+) CD4 (+) regulatory cells that control intestinal inflammation. J Exp Med 192: 295–302.
Real LM, Jimenez P, Kirkin A, Serrano A, Garcia A, Canton J, Zeuthen J, Garrido F, Ruiz-Cabello F (2001). Mechanism of immune evasion can coexist in melanoma tumor cell lines derived from the same patient. Cancer Immunol Immunother 49: 621–628.
Restifo NP, Esquivel F, Kawakami Y, Yewde JW, Mulé JJ, Rosenberg SA, Bennink JR (1993). Identification of human cancer deficient in antigen processing. J Exp Med 177: 265–272.
Roncarolo MG, Gregori S, Battaglia M, Bacchetta R, Fleischhauer K, Levings MK (2006). Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol 212: 28–50.
Rothlein RD (1986). A human intercellular adhesion molecule (ICAM-1) distinct from LFA-1. J Immunol 137: 1270–1274.
Sakaguchi S (2004). Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 22: 531–562.
Sakuishi K, Ngiow SF, Sullivan JM, Teng MWL, Kuchroo VK, Smyth MJ, Anderson AC (2013). TIM3+FOXP3+ regulatory T cells are tissue-specific promoters of T-cell dysfunction in cancer. Oncoimmunology 2: e23849.
Salazar-Onfray F, López MN, Mendoza-Naranjo A (2007). Paradoxical effects of cytokines in tumor immune surveillance and tumor immune escape. Cytokine Growth Factor Rev 18: 171–182.
Salomon B, Lenschow DJ, Rhee L, Ashourian N, Singh B, Sharpe A, Bluestone JA (2000). B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity 12: 431–440.
Sawanobori Y, Ueha S, Kurachi M, Shimaoka T, Talmadge JE, Abe J, Shono Y, Kitabatake M, Kakimi K, Mukaida N et al. (2008). Chemokine-mediated rapid turnover of myeloid-derived suppressor cells in tumor-bearing mice. Blood 111: 5457–5466.
Scheibenbogen C, Lee KH, Stevanovic S, Witzens M, Willhauck M, Waldmann V, Naeher H, Rammensee HG, Keilholz U (1997). Analysis of the T-cell response to tumor and viral peptide antigen by an IFN gamma-ELISPOT assay. Int J Cancer 71: 932–936.
Schmielau J, Finn OJ (2001). Activated granulocytes and granulocyte- derived hydrogen peroxide are the underlying mechanism of suppression of T-cell function in advanced cancer patients. Cancer Res 61: 4756–4760.
Schneider H, Valk E, da Rocha Dias S, Wei B, Rudd CE (2005). CTLA-4 up-regulation of lymphocyte function-associated antigen 1 adhesion and clustering as an alternate basis for coreceptor function. P Natl Acad Sci USA 102: 12861–12866.
Serafini P, Meckel K, Kelso M, Noonan K, Califano J, Koch W, Dolcetti L, Bronte V, Borrello I (2006). Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function. J Exp Med 203: 2691–2702.
Serafini P, Mgebroff S, Noonan K, Borrello I (2008). Myeloid-derived suppressor cells promote cross-tolerance in B-cell lymphoma by expanding regulatory T cells. Cancer Res 68: 5439–5449.
Seyerl M, Kirchberger S, Majdic O, Seipelt J, Jindra C, Schrauf C, Stockl J (2011). Human rhinoviruses induce IL-35-producing Treg via induction of B7–H1 (CD274) and sialoadhesin (CD169) on DC. Eur J Immunol 40: 321–329.
Shankaran V, Ikeda H, Bruce AT, White JM, Swanson PE, Old LJ, Schreiber RD (2001). IFNγ and lymphocytes prevent primary tumor development and shape tumor immunogenicity. Nature 410: 1107–1111.
Shimizu K, Nakata M, Hirami Y, Yukawa T, Maeda A, Tanemoto K (2010). Tumor infiltrating Foxp3+ regulatory T cells are correlated with cyclooxygenase-2 expression and are associated with recurrence in resected non-small cell lung cancer. J Thorac Oncol 5: 585–590.
Sinha P, Clements VK, Fulton AM, Ostrand-Rosenberg S (2007). Prostaglandin E2 promotes tumor progression by inducing myeloid-derived suppressor cells. Cancer Res 67: 4507–4513.
Smyth MJ, Dunn GP, Schreiber RD (2006). Cancer immunosurveillance and immunoediting: the roles of immunity in suppressing tumor development and shaping tumor immunogenicity. Adv Immunol 90: 1–50.
Szkaradkiewicz A, Karpiński TM, Drews M, Borejsza-Wysocki M, Majewski P, Andrzejewska E (2010). Natural killer cell cytotoxicity and immunosuppressive cytokines (IL- 10, TGF-β1) in patients with gastric cancer. J Biomed Biotechnol 2010: 901564.
Tai X, Van Laethem F, Pobezinsky L, Guinter T, Sharrow SO, Adams A, Granger L, Kruhlak M, Lindsten T, Thompson CB et al. (2012). Basis of CTLA-4 function in regulatory and conventional CD4 (+) T cells. Blood 119: 5155–5163.
Takahashi T, Tagami T, Yamazaki S, Uede T, Shimizu J, Sakaguchi N, Mak TW, Sakaguchi S (2000). Immunologic self- tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen. J Exp Med 192: 303–310.
Tan MC, Goedegebuure PS, Belt BA, Flaherty B, Sankpal N, Gillanders WE, Eberlein TJ, Hsieh CS, Linehan DC (2009). Disruption of CCR5-dependent homing of regulatory T cells inhibits tumor growth in a murine model of pancreatic cancer. J Immunol 182: 1746–1755.
Tang XL, Smith TR, Kumar V (2005). Specific control of immunity by regulatory CD8 T cells. Cell Mol Immunol 2: 11–19.
Tao H, Mimura Y, Aoe K, Kobayashi S, Yamamoto H, Matsuda E, Okabe K, Matsumoto T, Sugi K, Ueoka H (2012). Prognostic potential of FOXP3 expression in non-small cell lung cancer cells combined with tumor-infiltrating regulatory T cells. Lung cancer 75: 95–101.
Tsuchiya Y, Igarashi M, Suzuki R, Kumagai K (1988). Production of colony-stimulating factor by tumor cells and the factor- mediated induction of suppressor cells. J Immunol 141: 699– 708.
Tsuruta N, Yatsunami J, Takayama K, Nakanishi Y, Ichinose Y, Hara N (1998). Granulocyte-macrophage-colony stimulating factor stimulates tumor invasiveness in squamous lung carcinoma. Cancer 82: 2173–2183.
Waldhauer I, Steinle A (2008). NK cells and cancer immunosurveillance. Oncogene 27: 5932–5943.
Walsh GM, Williamson ML, Symon FA, Willars GB, Wardlaw AJ (1996). Ligation of CD69 induces apoptosis and cell death in human eosinophils cultured with granulocyte-macrophage colony-stimulating factor. Blood 87: 2815–2821.
Wang Z, Liu JQ, Liu Z, Shen R, Zhang G, Xu J, Basu S, Feng Y, Bai XF (2013). Tumor derived IL-35 promotes tumor growth by enhancing myeloid cell accumulation and angiogenesis. J Immunol 190: 2415–2423.
Wei S, Kryczek I, Zou L, Daniel B, Cheng P, Mottram P, Curiel T, Lange A, Zou W (2005). Plasmacytoid dendritic cells induce CD8+ regulatory T cells in human ovarian carcinoma. Cancer Res 65: 5020–5026.
Wen QS, Zhang GZ, Kong XT (1994). Modulation effect of cimetidine on the production of IL-2 and interferon-γ in patients with gastric cancer. Zhonghua Zhong Liu Za Zhi 16: 299–301 (in Chinese with English abstract).
Wiers KM, Lathers DM, Wright MA, Young MR (2000). Vitamin D3 treatment to diminish the levels of immune suppressive CD34 cells increases the effectiveness of adoptive immunotherapy. J Immunother 23: 115–124.
Wigmore SJ, Fearon KCH, Maingay JP, Lai P, Ross JA (1997). Interleukin-8 can mediate acute-phase protein production by isolated human hepatocytes. Am J Physiol 273: 720–726.
Wild CA, Brandau S, Lindemann M, Lotfi R, Hoffmann TK, Lang S, Bergmann C (2010). Toll-like receptors in regulatory T cells of patients with head and neck cancer. Arch Otolaryngol Head Neck Surg 136: 1253–1259.
Wölfel T, Klehmann E, Müller C, Schütt KH, Meyer zum Büschenfelde KH, Knuth A (1989). Lysis of human melanoma cells by autologous cytolytic T cells clones. Identification of human histocompatibility leukocyte antigen A2 as a restriction element for three different antigens. J Exp Med 170: 797–810.
Xu S, Wen Z, Jiang Q, Zhu L, Feng S, Zhao Y, Wu J, Dong Q, Mao J, Zhu Y (2014). CD58, a novel surface marker, promotes self-renewal of tumor-initiating cells in colorectal cancer. Oncogene (in press).
Yang ZZ, Novak AJ, Ziesmer SC, Witzig TE, Ansell SM (2007). CD70+ non-Hodgkin lymphoma B cells induce Foxp3 expression and regulatory function in intratumoral CD4+CD25 T cells. Blood 110: 2537–2544.
Yasushi O, Zoltan F, Tomoyuki Y, Shimon S (2008). Foxp3+ natural regulatory T cells preferentially form aggregates on dendritic cells in vitro and actively inhibit their maturation. P Natl Acad Sci USA 105: 10113–10118.
Ye J, Ma C, Hsueh EC, Eickhoff CS, Zhang Y, Varvares MA, Hoft DF, Peng G (2013). Tumor-derived γδ regulatory T cells suppress innate and adaptive immunity through the induction of immunosenescence. J Immunol 190: 2403–2414.
Yuan XL, Chen L, Zhang TT, Ma YH, Zhou YL, Zhao Y, Wang WW, Dong P, Yu L, Zhang YY et al. (2011). Gastric cancer cells induce human CD4+Foxp3+ regulatory T cells through the production of TGF-β1. World J Gastroenterol 17: 2019–2027.
Zambon CF, Basso D, Navaglia F, Belluco C, Falda A, Fogar P, Greco E, Gallo N, Rugge M, Di Mario F et al. (2005). Pro- and antiinflammatory cytokines gene polymorphisms and Helicobacter pylori infection: interactions influence outcome. Cytokine 29: 141–152.
Zea AH, Rodriguez PC, Atkins MB, Hernandez C, Signoretti S, Zabaleta J, McDermott D, Quiceno D, Youmans A, O’Neill A et al. (2005). Arginase-producing myeloid suppressor cells in renal cell carcinoma patients: a mechanism of tumor evasion. Cancer Res 65: 3044–3048.
Zhao X, Wang X, Chang Y, Zhao X, Zhang X, Liu D, Xu L, Liu K , Huan X (2013). Non-traditional CD4+ CD25–CD69+ regulatory T cells is correlated to leukemia relapse after allogeneic hematopoietic stem cell transplantation. Blood 122: 3259.
Zhou H, Chen L, You Y, Zou L, Zou P (2010). Foxp3-transduced polyclonal regulatory T cells suppress NK cell functions in a TGF-beta dependent manner. Autoimmunity 43: 299–307.