肿瘤微环境中靶向调节性T细胞免疫治疗策略

摘要

调节性T细胞(Treg)是一群具有负调节机体免疫反应的淋巴细胞.可抑制肿瘤相关抗原T细胞免疫,影响肿瘤免疫治疗效果以及疫苗活化.清除CD4+CD25+T细胞(Treg)可抑制肿瘤生长,但会引起自身免疫性疾病,这与Treg细胞维持自身免疫耐受有关.Treg根据来源可分为胸腺来源的天然调节性T细胞(nTreg)和外周诱导型调节性T细胞(iTreg).虽然调节性T细胞在不同癌症类型和组织中表型多样且具有异质性,但都共表达CD4、CD25、foxp3分子标记.由于其肿瘤异质性和器官异质性,因此在肿瘤免疫治疗中靶向Treg细胞策略也不同.肿瘤免疫治疗中可清除Treg或清除限制Treg细胞免疫抑制的功能蛋白例如GITR、T-bet、Neoropilin-1、CTLA-4、IDO或PD-1.在清除Treg细胞时为防止引起自身免疫性疾病通常加入OVA疫苗;目前已获FDA批准Ipilimumab治疗黑色素瘤的分子机制就是靶向Treg细胞的CTLA-4.本文通过对Treg的表型、异质性及靶向Treg的肿瘤治疗策略的综述,为将来针对Treg治疗时,避免免疫紊乱提供研究思路.%Regulatory T cell (Treg) is a group of lymphocytes with negetive regulation of inhibiting tumor-associated antigen T cell-mediated immune responses,targeted agents may influence tumor immunotherapy and vaccine activation.Systemic removal of CD25+CD4+ T cells perhaps elicit tumor growth in rodents,but also increasing the severity of the autoimmune diseases as peripheral self-tolerance is maintained by Treg cells.According to sources of Regulatory T cells,it can be classfied as two population of nTreg and iTreg cells.Regulatory T cells are phenotypically diversity and functionally heterogeneous in different types of tumor and tissues,whereas conferring the same marker of CD4,CD25 and foxp3.Because of its tumor heterogeneity and organ heterogeneity,therefore,the strategy of targeting Treg cells in tumor immunotherapy is different.On the other hand,removal Treg cell strategies is different in tumor immunotherapy,it can remove regulatory T cells (Treg) or dampen the function of Treg cells through limit its immunosuppression protein,such as GITR,T-bet,Neoropilin-1,CTLA-4,IDO or PD-1.The autoimmunities can be prevented by inoculating OVA vaccine when removing Tregs.Ipilimumab,which has recently been FDA-approved for therapy patients with advanced melanoma mechnism is targeting CTLA-4 in Treg cells.In this paper,we review the phenotype,heterogeneity and tumor therapy strategies of Treg treatment in order to avoid immune disorders in the future.