国自然调节性T细胞介导的免疫逃逸在肿瘤中的作用

1、调节性T细胞（Treg ）介导的免疫逃逸在肿瘤中的作用调节性T细胞（regulatory T cells, Treg）是一群具有免疫抑制功能的T细胞，主 要分为天然型Treg（CD4+CD25+Treg）和诱导型Treg（iTreg）两大类。Treg在慢性免疫 应答中可以限制自身免疫造成的组织损伤，但却也给肿瘤逃避机体的免疫创造了条件。Treg 能够通过以下多种途径抑制机体免疫反应，促使肿瘤细胞发生免疫耐受逃逸：（1）Treg通 过分泌多种抑制性细胞因子，如TGF-8、IL-10、IL-35等，发挥免疫抑制效应1；（2）Treg 表面组成性表达CD25（IL2Ra链），能与效应T细胞竞争性结合

2、并大量消耗IL-2,从而抑 制效应细胞（如CD4+和CD8+T淋巴细胞）的增殖2；（3）Treg表面组成性表达CTLA-4，能 与树突细胞（DC）表面配体CD80和CD86相互作用，从而阻断它们的共刺激功能和随后的T 细胞活化和功能3；（4）在肿瘤微环境中Treg可以表达颗粒酶B，以颗粒酶B/穿孔素依赖 的方式使NK、CTL等细胞溶解，抑制机体抗肿瘤免疫4。iTreg细胞由多种成分在外周诱导 产生，主要以细胞因子依赖（IL-10和TGF-p ）发挥免疫负调节作用。CD4+CD25+Treg特异性表达转录因子FOXP3, FOXP3在Treg的分化发育及其介导的肿 瘤免疫逃逸中发挥关键作用，因而

3、是鉴别肿瘤微环境中Treg的有效靶标5。预防性Foxp3 DNA /重组蛋白疫苗（Foxp3疫苗）在无肿瘤条件下促进针对Treg的免疫性，通过靶向Treg和 MDSC来促进针对肿瘤的免疫应答，这可以被用作潜在的免疫治疗方法6。越来越多的研究表 明Treg介导的免疫监视逃逸在肿瘤的发生发展过程中发挥着重要作用7, 8。Treg已被发现 在肿瘤患者外周血和肿瘤组织中过量增加，包括乳腺癌9、肠癌10、胃癌11、白血病12、黑色 素瘤13、非小细胞肺癌14、卵巢癌15和肝癌16。大多数证据表明肿瘤微环境中Treg高表达和 预后不良有关。然而Fridman等研究发现，结直肠癌患者肿瘤组织浸润高密度的 F

4、OXP3+Treg细胞提示患者的预后较好直，这可能是和肿瘤类型、Treg的分布和定位有关。 尽管如此，目前人们普遍认为活的Treg细胞抑制抗肿瘤免疫18，因而它成为了肿瘤免疫治 疗的新方向。如，有研究发现后萎缩性增生（PAH）在CD4 + Tregs存在下直接进入前列腺 癌的可能途径，并且表明即使在原发性肿瘤建立之前，抗肿瘤免疫应答的转化也可能开始19。 抗CTLA-4单抗，在II期临床试验中能有效延长IV期黑色素瘤患者的存活时间。能够阻断 体外CCL22-介导的Treg和Th2招募过程的小分子趋化因子受体拮抗剂或单抗也已进入I期 临床试验阶段20。在肾细胞癌中，由新的肽拮抗剂肽-R29引发的

5、CXCR4拮抗作用能有效地逆 转Teff增殖的Treg抑制，这可能是肿瘤免疫应答的可靠生物标志物21。最近一些研究为Treg的免疫抑制功能提供了新的机制。Vizio等发现FoxP3+Treg细胞 参与Th17启动的癌变过程22。Treg抑制宫颈癌肿瘤微环境中存在的肿瘤浸润Th1和Th2效 应分子23。此外，FOXP3 +调节性T细胞包括不同亚群，其中CXCR3+ Treg细胞，已被证明 特异性地控制体内的I型T细胞反应。Redjimi等发现CXCR3+ Treg细胞高度富集于人类卵 巢癌，特别是在实体肿瘤中，控制I型T细胞应答，导致免疫抑制24。HIV感染诱导CD8 + CD28-CD127l

6、oCD39 + Treg细胞的显着扩增，其频率与临床疾病和慢性免疫细胞活化的迹象 相关25。综上，关于Treg细胞与肿瘤的关系以及作用机制还有待深入的研究，以此为肿瘤的免 疫治疗提供更多新的思路，为肿瘤的治疗带来新的突破。参考文献Kanamori M, Nakatsukasa H, Okada M, Lu Q, Yoshimura A. Induced Regulatory T Cells: Their Development, Stability, and Applications. Trends in immunology2016.Sakaguchi S, Miyara M, Costan

7、tino CM, Hafler DA. FOXP3+ regulatory T cells in the human immune system. Nature reviews Immunolog以010; 10(7): 490-500.Menetrier-Caux C, Curiel T, Faget J, Manuel M, Caux C, Zou W. Targeting regulatory T cells. Targeted oncology2012; 7(1): 15-28.Cao X, Cai SF, Fehniger TA, et al. Granzyme B and perf

8、orin are important for regulatory T cell-mediated suppression of tumor clearance. Immunity 2007; 27(4): 635-46.Plitas G, Rudensky AY. Regulatory T Cells: Differentiation and Function. Cancer immunology research2016; 4(9): 721-5.Namdar A, Mirzaei R, Memarnejadian A, et al. Prophylactic DNA vaccine ta

9、rgeting Foxp3+ regulatory T cells depletes myeloid-derived suppressor cells and improves anti-melanoma immune responses in a murine model. Cancer immunology, immunotherapy: CII 2017.Park J, Kwon M, Shin EC. Immune checkpoint inhibitors for cancer treatment. Archives of pharmacal researc!2016.Camisas

10、chi C, Vallacchi V, Vergani E, et al. Targeting Immune Regulatory Networks to Counteract Immune Suppression in Cancer. Vaccines 2016; 4(4).through CCL22/CCR4 are selectively activated in lymphoid infiltrates surrounding primary breast tumors and lead to an adverse clinical outcome. Cancerresearch200

11、9; 69 (5): 2000-9.Kryczek I, Liu R, Wang G, et al. FOXP3 defines regulatory T cells in human tumor and autoimmune disease. Cancer research2009; 69 (9): 3995-4000.Ichihara F, Kono K, Takahashi A, Kawaida H, Sugai H, Fujii H. Increased populations of regulatory T cells in peripheral blood and tumor-in

12、filtrating lymphocytes in patients with gastric and esophageal cancers. Clinical cancer research: an official journalof the AmericanAssociationfor CancerResearch2003; 9(12): 4404-8.Karube K, Ohshima K, Tsuchiya T, et al. Expression of FoxP3, a key molecule in CD4CD25 regulatory T cells, in adult T-c

13、ell leukaemia/lymphoma cells. British journal of haematology2004; 126(1): 81-4.Viguier M, Lemaitre F, Verola O, et al. Foxp3 expressing CD4+CD25(high) regulatory T cells are overrepresented in human metastatic melanoma lymph nodes and inhibit the function of infiltrating T cells.Journal of immunolog

14、*004; 173 (2): 1444-53.Li L, Chao QG, Ping LZ, et al. The prevalence of FOXP3+ regulatory T-cells in peripheral blood of patients with NSCLC.Cancer biotherapy & radiopharmaceuticals 2009; 24 (3): 357-67.Woo EY, Chu CS, Goletz TJ, et al. Regulatory CD4(+)CD25(+) T cells in tumors from patients with e

15、arly-stage non-small cell lung cancer and late-stage ovarian cancer. Cancer research2001; 61 (12): 4766-72.Yang J, Zhang JX, Wang H, Wang GL, Hu QG, Zheng QC. Hepatocellular carcinoma and macrophage interaction induced tumor immunosuppression via Treg requires TLR4 signaling. World journal of gastro

16、enterology : WJ2012; 18(23): 2938-47.Fridman WH, Galon J, Pages F, Tartour E, Sautes-Fridman C, Kroemer G. Prognostic and predictive impact of intra- and peritumoral immune infiltrates. Cancer research 2011; 71(17): 5601-5.apoptosis and suppressor activity and PD-L1-blockade resistance in tumor. 201

17、7.Davidsson S, Andren O, Ohlson AL, et al. FOXP3+ regulatory T cells in normal prostate tissue, postatrophic hyperplasia, prostatic intraepithelial neoplasia, and tumor histological lesions in men with and without prostate cancer. The Prostate 2017.Yamamoto K, Utsunomiya A, Tobinai K, et al. Phase I

18、 study of KW-0761, a defucosylated humanized anti-CCR4 antibody, in relapsed patients with adult T-cell leukemia-lymphoma and peripheral T-cell lymphoma. Journal of clinical oncology : official journal of the American Society of ClinicalOncology2010; 28 (9): 1591-8.Santagata S, Napolitano M, D,Alter

19、io C, et al. Targeting CXCR4 reverts the suppressive activity of T-regulatory cells in renal cancer. Oncotarget2017; 8 (44): 77110-20.Vizio B, Novarino A, Giacobino A, et al. Potential plasticity of T regulatory cells in pancreatic carcinoma in relation to disease progression and outcome. Experimental and therapeutic medicin2012; 4(1): 70-8.Adurthi S, Mukherjee G, Krishnamurthy