JJIAO 36 1 : 35 39, 2018 総説 T T regulatory T cell, Treg Treg IL-10 TGF-β Treg Treg CTLA-4 Treg PD-1 T effector T helper T NK/NKT

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1 JJIAO 36 1 : 35 39, 2018 総説 T T regulatory T cell, Treg Treg IL-10 TGF-β Treg Treg CTLA-4 Treg PD-1 T effector T helper T NK/NKT TEL: yoriorita@kumamoto-u.ac.jp dendritic cell, DC Major Histocompatibility Complex MHC = human leukocyte antigen; HLA I II cross-presentation T 1) 1 MHC HLA 1980 T MHC HLA I 1996 DC ) 2018 Japan Society of Immunology & Allergology in Otolaryngology

36 折田熊本大学図2 頼尚頭頸部がんと制御性 T 細胞図 1 T 細胞による抗腫瘍免疫応答の発現生命資源研究支援センター西村泰治先生よりご提供抗体を介して免疫細胞が腫瘍細胞を殺傷するしくみ Nat Rev Cancer 2012; 12(4): 278 87 より引用用補体の活性化抗体依存性細胞傷害 antibody-dependent

免疫現象の発生を抑える生体防御反応である免疫チェッのような T-cell inhibitory receptors の阻害等によってなさクポイントについては近年多くの論文総説で解説されてれる ADCC にあたるものが Rituximab や Cetuximab でありいるためここではあえて詳細は述べないが CTLA-4 は T 抗 CTLA-4 抗

2 36 折田熊本大学図2 頼尚頭頸部がんと制御性 T 細胞図 1 T 細胞による抗腫瘍免疫応答の発現生命資源研究支援センター西村泰治先生よりご提供抗体を介して免疫細胞が腫瘍細胞を殺傷するしくみ Nat Rev Cancer 2012; 12(4): より引用用補体の活性化抗体依存性細胞傷害 antibody-dependent cellular cytotoxicity ADCC 一本鎖抗体による遺伝子改変を受けた T 細胞前述の DC による抗原提示を受けた T 細 T 細胞の免疫抑制解除による抗腫瘍免疫の増強免疫チェックポイントは過剰な免疫反応を抑制し自己胞そして cytotoxic T lymphocyte-associated antigen 4 CTLA4 免疫現象の発生を抑える生体防御反応である免疫チェッのような T-cell inhibitory receptors の阻害等によってなさクポイントについては近年多くの論文総説で解説されてれる ADCC にあたるものが Rituximab や Cetuximab でありいるためここではあえて詳細は述べないが CTLA-4 は T 抗 CTLA-4 抗 programmed cell death 1 PD-1 作用のような細胞が DC から抗原提示を受けて活性化される際に PD-1 checkpoint を阻害することによって抗腫瘍効果を狙ったもは活性化した T 細胞ががん細胞を攻撃する際にそれぞれのが Ipilimumab や Nivolumab である T 細胞の活性化を抑制する信号を発する分子として知られ

3 JJIAO 2018: CTLA-4 CD28 CD80 CD86 CTLA-4 CD CD80 CD86 T 3) CTLA-4 T regulatory T cell, Treg CTLA-4 T 2 3 4) PD-1 PD-1 5) PD-1 I 6) PD-1 PDL-1 6) T CTLA-4 PD-1 PDL-1 3 CTLA-4/PD-1 7) CTLA-4/PD-L1 III T Treg naturally occurring Treg 2 Treg 8,9) subset Treg cell-cell contact interleukin 10 IL-10 transforming growth factor-β TGF-β 10) IL-10 TGF-β 11,12) IL10 MHC class II MHC class I downregulation 13) TGF-β 14 16) Treg 17 20) Treg 21,22) Treg 23) Treg Treg Cyclooxygenase COX prostaglandin PG mediator 24) COX COX-1 COX-2 isoform COX-1 COX-2 25) COX-2 PGE2 CD4 Forkhead box P3 Foxp3 Treg 26,27) COX-2 Treg 28) Treg effector T COX-2 PGE2 29) nonsteroidal anti-inflammatory drug NSAID Treg 30) COX-2 4-nitroquinoline-1-oxide 4NQO 4NQO 31) 32) % Treg COX-2 celecoxib Treg 33) Treg COX-2 Treg CC chemokine receptor 4 CCR4 CCR4 Treg T 34) CCR4 Mogamulizumab Treg 35) PD-1 T

4 38 T 36) T Treg CTLA-4 T 37) PD-1 CTLA-4 CCR4 Treg 1) Topalian SL, Rivoltini L, et al. Melanoma-specific CD4+ lymphocytes recognize human melanoma antigens processed and presented by Ebstein-Barr virus-transformed B cells. Int J Cancer. 1994; 58(1): ) Scott AM, Wolchok JD, et al. Antibody therapy of cancer. Nat Rev Cancer. 2012; 12(4): ) Greenwald RJ, Freeman GJ, et al. The B7 family revisited. Annu Rev Immunol. 2005; 23: ) Waterhouse P, Penninger JM, et al. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science. 1995; 270(5238): ) Nishimura H, Nose M, et al. Development of lupus-like auto immune diseases by disruption of the PD-1 gene encoding an ITIM motifcarrying immunoreceptor. Immunity. 1999; 11(2): ) 2016; 256(7): ) Larkin J, Chiarion-Sileni V, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015; 373(1): ) Roncarolo MG, Bacchetta R, et al. Type 1 T regulatory cells. Immunol Rev. 2001; 182: ) Weiner HL. Induction and mechanism of action of thransforming growth factor-beta-secreting Th3 reglatory cells. Immunol Rev. 2001; 182: ) Shevach EM. CD4+CD25+ suppressor T cells: more questions than answers. Nat Rev Immunol. 2002; 2(6): ) Larmonier N, Marron M, et al. Tumor-derived CD4(+)CD25(+) regulatory T cell suppression of dendritic cell function involves TGF-beta and IL-10. Cancer Immunol Immunother. 2007; 56(1): ) Yu P, Lee Y, et al. Intratumor depletion of CD4 + cells unmasks tumor immunogenicity leading to the rejection of late-stage tumors. J Exp Med. 2005; 201(5): ) Mannino MH, Zhu Z, et al. The paradoxical role of IL-10 in immunity and cancer. Cancer Lett. 2015; 367(2): ) Massagué J, Blain SW, et al. TGF-beta signaling in growth control, cancer and heritable disorders. Cell. 2000; 103(2): ) Han G, Wang XJ. Roles of TGF-β signaling Smads in squamous cell carcinoma. Cell Biosci. 2011; 1: ) Oshimori N, Oristian D. TGF-β promotes heterogeneity and drug resistance in squamous cell carcinoma. Cell. 2015; 160(5): ) Curiel TJ, Coukos G, et al. Specific recruitment of regulatory T cells in ovalian carcinoma fosters immune privilege and predicts reduced survival. Nat Med. 2004; 10(9): ) Hiraoka N, Onozato K, et al. Prevalence of FOXP3+ regulatory T cells increases during the progression of pancreatic ductal adenocarcinoma and its premalignant lesions. Clin Cancer Res. 2006; 12(18): ) Katz SC, Bamboat ZM, et al. Regulatory T cell infiltration predicts outcome following resection of colorectal cancer liver metastases. Ann Surg Oncol. 2013; 20(3): ) Viguier M, Lemaitre F, et al. Foxp3 expressing CD4+CD25(high) regulatory T cells are overexpressed in human metastatic melanoma lymph nodes and inhibit the function of infiltrating T cells. J Immunol. 2004; 173(2): ) Albers AE, Ferris RL, et al. Immune responses to p53 in patients with cancer: enrichment in tetramer+ p53 peptide-specific T cells and regulatory T cells at tumor sites. Cancer Immunol Immunother. 2005; 54(11): ) Strauss L, Bergmann C, et al. A unique subset of CD4 + CD25 high Foxp3 + T cells secreting interleukin-10 and transforming growth factor-β1 mediates suppression in the tumor microenvironment. Clin Cancer Res. 2007; 13(15 Pt 1): ) Hanakawa H, Orita Y, et al. Regulatory T-cell infiltration in tongue squamous cell carcinoma. Acta Otolaryngol. 2014; 134(8): ) Crofford LJ. COX-1 and COX-2 tissue expression: implications and predictions. J Rheumatol. 1997; 24 (Suppl 49): ) Hla T, Neilson K. Human cyclooxygenase-2 cdna. Proc Natl Acad Sci U S A. 1992; 89(16): ) Baratelli F, Lin Y, et al. Prostaglandin E2 induces FOXP3 gene expression and T regulatory cell function in human CD4+ T cells. J Immunol. 2005; 175(3): ) Mahic M, Yaqub S, et al. FOXP3+CD4+CD25+ adaptive regulatory T cells express cyclooxygenase-2 and suppress effector T cells by a prostaglandin E2-dependent mechanism. J Immunol. 2006; 177(1): ) Sun DS, Zhaq MQ, et al. The correlation between tumor-infiltrating Foxp3+ regulatory T cells and cyclooxygenase-2 expression and their association with recurrence in resected head and neck cancers. Med Oncol. 2012; 29(2): ) Yuan XL, Chen L, et al. Elevated expression of Foxp3 in tumorinfiltrating Treg cells suppresses T-cell proliferation and contributes to gastric cancer progression in a COX-2-dependent manner. Clin Immunol. 2010; 134(3): ) Badoual C, Hans S, et al. Prognostic value of tumor-infiltrating CD4+ T-cell subpopulations in head and neck cancers. Clin Cancer Res. 2006; 12(2): ) Vitale-Cross L, Czerninski R, et al. Chemical carcinogenesis models for evaluating molecular-targeted prevention and treatment of oral cancer. Cancer Prev Res (Phila). 2009; 2(5): ) Tang XH, Knudsen B, et al. Oral cavity and esophageal carcinogenesis modeled in carcinogen-treated mice. Clin Cancer Res. 2004; 10(1 Pt 1):

5 JJIAO 2018: ) Miki K, Orita Y, et al. Regulatory T cells function at the early stage of tumor progression in a mouse model of tongue squamous cell carcinoma. Cancer Immunol Immunother. 2016; 65(11): ) Iellem A, Mariani M, et al. Unique chemotactic response profile and specific expression of chemokine receptors CCR4 and CCR8 by CD4(+)CD25(+) regulatory T cells. J Exp Med. 2001; 194(6): ) Sugiyama D, Nishikawa H, et al. Anti-CCR4 mab selectively depletes effector-type FoxP3+CD4+regulatory T cells, evoking antitumor immune responses in humans. Proc Natl Acad Sci U S A. 2013; 110(44): ) Okazaki T, Honjo T. PD-1 and PD-1 ligands: from discovery to clinical application. Int Immunol. 2007; 19(7): ) Vetizou M, Pitt JM, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science. 2015; 7(271): 271ps1. Regulatory T cells in head and neck cancer Yorihisa Orita Department of Otolaryngology-Head and Neck Surgery, Kumamoto University Graduate School of Medical Sciences Abstract Regulatory T cells (Tregs) engage in the maintenance of immunological self-tolerance by suppressing self-reactive lymphocytes. This mechanism for maintaining immunological self-tolerance may hinder effective tumor immunity. In various kinds of cancer, accumulation of Tregs in the tumor site is associated with a reduction in patients survival, while blockade of the effects of IL-10 and TGF-β reverses the Treg function and enhances antitumor immunity. However, we cannot conclude that Tregs always have a promotive role during the development of cancer because the microscopic environment of cancer will change depending on the kinds and the stage of cancer. Since CTLA-4 antibody may be available for head and neck cancer, we should undergo Treg suppression therapy as well as PD-1 blockade therapy in the most effective way. Key words: regulatory T cell, immunological self-tolerance, microscopic environment of cancer, the most effective way

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Untitled 上原記念生命科学財団研究報告集, 23(2009) 190. CD4 + ヘルパー T 細胞の選択的活性化西川博嘉 Key words:cd4 + ヘルパー T 細胞,CD4 + 制御性 T 細胞, 癌精巣抗原,co-stimulatory molecules, 抗体療法三重大学大学院医学系研究科寄付講座がんワクチン講座緒言 1991 年ヒト腫瘍抗原遺伝子の存在が報告されて以来, これらの腫瘍特異抗原を用いた悪性腫瘍に対する免疫療法が注目を集めている.

JJIAO 36 1 : 35 39, 2018 総 説 T T regulatory T cell, Treg Treg IL-10 TGF-β Treg Treg CTLA-4 Treg PD-1 T effector T helper T NK/NKT

JJIAO 36 1 : 35 39, 2018 総説 T T regulatory T cell, Treg Treg IL-10 TGF-β Treg Treg CTLA-4 Treg PD-1 T effector T helper T NK/NKT