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，主要包括天然型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-B、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

2、合并大量消耗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-B )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

3、用，因而是鉴别肿瘤微环境中Treg的 有效靶标5。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。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6、肠癌7、胃癌8、白血病9、黑色素瘤10、非小细胞肺癌11、卵 巢癌12和肝癌13。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，Treg浸润到肿瘤内部和周围却没有显著作用，甚至是对患者有益的，这 可能和肿瘤类型，Treg分布和定位有关。如Fridman等研究发现，结直肠癌患 者肿瘤组织浸润高密度的FOXP3+Treg细胞提示患者的预后较好14。尽管如此， 目前人们普遍认为Tr

4、eg浸润的肿瘤抑制免疫干预的疗效，因而成为肿瘤免疫治 疗的新方向。如抗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15。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16。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17。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。 Redjim

5、i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18。综上，关于Treg细胞与肿瘤的关系以及作用机制有待深入研究，为肿瘤的 免疫治疗提供更多新的思路，从而为肿瘤的治疗带来新的突破。参考文献Strauss L, Bergmann C, Szczepanski M, Gooding W, Johnson JT, Whiteside TL. A unique subset of CD4+CD25highFoxp3+ T cells secreting interleukin-10 and transforming growth facto

6、r-beta1 mediates suppression in the tumor microenvironment. Clinical cancer research : an official journal of the American Association for Cancer Research007; 13(15 Pt 1): 4345-54.Sakaguchi S, Miyara M, Costantino CM, Hafler DA. FOXP3+ regulatory T cells in the human immune system. Nature reviews Im

7、munology2010; 10(7): 490-500.Menetrier-Caux C, Curiel T, Faget J, Manuel M, Caux C, Zou W. Targeting regulatory T cells. Targeted oncology?012; 7(1): 15-28.Cao X, Cai SF, Fehniger TA, et al. Granzyme B and perforin are important for regulatory T cell-mediated suppression of tumor clearance. Immunity

8、2007;27(4): 635-46.Kryczek I, Wu K, Zhao E, et al. IL-17+ regulatory T cells in the microenvironments of chronic inflammation and cancer. Journal of immunology2011; 186(7): 4388-95.Gobert M, Treilleux I, Bendriss-Vermare N, et al. Regulatory T cells recruited through CCL22/CCR4 are selectively activ

9、ated in lymphoid infiltrates surrounding primary breast tumors and lead to an adverse clinical outcome. Cancer research2009; 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

10、, Takahashi A, Kawaida H, Sugai H, Fujii H. Increased populations of regulatory T cells in peripheral blood and tumor-infiltrating lymphocytes in patients with gastric and esophageal cancers. Clinical cancer research : an official journal of the American Association for Cancer Research 2003; 9(12):

11、4404-8.Karube K, Ohshima K, Tsuchiya T, et al. Expression of FoxP3, a key molecule in CD4CD25 regulatory T cells, in adult T-cell leukaemia/lymphoma cells. British journal of haematolog%004; 126(1): 81-4.Viguier M, Lemaitre F, Verola O, et al. Foxp3 expressing CD4+CD25(high) regulatory T cells are o

12、verrepresented in human metastatic melanoma lymph nodes and inhibit the function of infiltrating T cells. Journal of immunolog%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 & radiopharmace

13、utical2009;24(3): 357-67.Woo EY, Chu CS, Goletz TJ, et al. Regulatory CD4(+)CD25(+) T cells in tumors from patients with early-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 carc

14、inoma and macrophage interaction induced tumor immunosuppression via Treg requires TLR4 signaling. World journal of gastroenterology : WJG012; 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 infil

15、trates. Cancer research2011; 71 (17): 5601-5.Yamamoto K, Utsunomiya A, Tobinai K, et al. Phase I 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

16、 the American Society of Clinical Oncology)10; 28(9): 1591-8.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 H, et al. Functional tumor infiltratingTH1 and TH2 effectors in large early-stage cervical cancer are suppressed by regulatory T cells. International journal of gynecological cancer : of