Tumor-infiltrating human CD4+ regulatory T cells display a distinct TCR repertoire and exhibit tumor and neoantigen reactivity
Tumor-infiltrating human CD4+ regulatory T cells display a distinct TCR repertoire and exhibit tumor and neoantigen reactivity
复制标题
DOI：
10.1126/sciimmunol.aao4310
复制
发表时间：
2019-01-01
影响因子：
24.8
通讯作者：
Rosenberg, Steven A.
中科院分区：
文献类型：
--
作者：
Ahmadzadeh, Mojgan;Pasetto, Anna;Rosenberg, Steven A.
CD4（+）调节性T （T-reg）细胞在维持自身耐受性方面具有重要功能；然而，它们也可能在抗肿瘤免疫反应中起不利作用。肿瘤中T-reg细胞频率升高与癌症患者的疾病进展和不良生存率相关。在肿瘤微环境中扩增的T-reg细胞的抗原特异性尚不清楚；回答这个问题可能为免疫治疗方法提供重要的见解。为了解决这个问题，我们使用了一种新的组合方法来表征转移性黑色素瘤、胃肠道和卵巢癌患者肿瘤内T-reg细胞的T细胞受体（TCR）谱，并阐明了它们的抗原特异性。肿瘤驻留T-reg细胞的TCR谱是多种多样的，但与循环T-reg细胞有显著的重叠，而与肿瘤或血液中的常规T细胞没有重叠。从T-reg细胞中分离出的tcr对自体肿瘤和突变的新抗原表现出特异性反应性，这表明肿瘤内T-reg细胞以肿瘤抗原选择性方式起作用，导致其在肿瘤微环境中激活和克隆扩增。肿瘤抗原特异性T-reg衍生的tcr存在于肿瘤和血液循环中，这表明这两种T-reg细胞区室都可能是肿瘤特异性tcr的来源。这些发现为肿瘤浸润的人类t - regg细胞的TCR特异性提供了见解，这可能对癌症免疫治疗有潜在的影响。
CD4(+) regulatory T (T-reg) cells have an essential function in maintaining self-tolerance; however, they may also play a detrimental role in antitumor immune responses. The presence of elevated frequencies of T-reg cells in tumors correlates with disease progression and poor survival in patients with cancer. The antigen specificity of T-reg cells that have expanded in the tumor microenvironment is poorly understood; answering this question may provide important insights for immunotherapeutic approaches. To address this, we used a novel combinatorial approach to characterizing the T cell receptor (TCR) profiles of intratumoral T-reg cells from patients with metastatic melanoma, gastrointestinal, and ovarian cancers and elucidated their antigen specificities. The TCR repertoires of tumor-resident T-reg cells were diverse yet displayed significant overlap with circulating T-reg cells but not with conventional T cells in tumor or blood. TCRs isolated from T-reg cells displayed specific reactivity against autologous tumors and mutated neoantigens, suggesting that intratumoral T-reg cells act in a tumor antigen-selective manner leading to their activation and clonal expansion in the tumor microenvironment. Tumor antigen-specific T-reg-derived TCRs resided in the tumor and in the circulation, suggesting that both T-reg cell compartments may serve as a source for tumor-specific TCRs. These findings provide insights into the TCR specificity of tumor-infiltrating human T-reg cells that may have potential implications for cancer immunotherapy.