Department of Pathology, University of Chicago, Chicago, Illinois.
The Committee on Immunology, University of Chicago, Chicago, Illinois.
Cancer Immunol Res. 2018 Jan;6(1):14-24. doi: 10.1158/2326-6066.CIR-17-0249. Epub 2017 Nov 2.
Subsets of human tumors are infiltrated with tumor antigen-specific CD8 T cells [tumor-infiltrating lymphocytes (TILs)] despite tumor progression. These TILs are thought to be inactivated by the immunosuppressive tumor microenvironment, through the engagement of inhibitory receptors such as CTLA-4 and PD-1. However, antigen-specific CD8 TILs are not functionally inert but are undergoing activation Here, we show that antigen-specific CD8 TILs are actively proliferating, yet also undergo high rates of apoptosis, leading to a vicious cycle of activation and death that limits immune efficacy. Preventing CD8 TIL apoptosis by Bcl-x overexpression enabled accumulation and improved tumor control. Effective combination immunotherapy with an agonist 4-1BB mAb plus either CTLA-4 or PD-L1 neutralization led to a marked accumulation of specific CD8 TILs through decreased apoptosis rather than increased T-cell entry or proliferation. Our data suggest that antigen-driven apoptosis of CD8 TILs is a barrier to effective spontaneous antitumor immunity and should be considered as a critical factor in the development of cancer immunotherapies. .
尽管肿瘤在不断进展，但是仍有一部分人类肿瘤被肿瘤抗原特异性 CD8 T 细胞（肿瘤浸润淋巴细胞（TILs））浸润。这些 TILs被认为被免疫抑制性肿瘤微环境通过结合抑制性受体如 CTLA-4 和 PD-1 而失活。然而，抗原特异性 CD8 TIL 并非功能上无活性，而是正在经历激活。在这里，我们发现抗原特异性 CD8 TIL 正在积极增殖，但也经历高比例的凋亡，导致激活和死亡的恶性循环，从而限制了免疫疗效。通过 Bcl-x 过表达防止 CD8 TIL 凋亡能够实现积累并改善肿瘤控制。使用激动剂 4-1BB mAb 联合 CTLA-4 或 PD-L1 中和的有效联合免疫疗法通过减少凋亡而非增加 T 细胞进入或增殖导致特定 CD8 TIL 的显著积累。我们的数据表明，抗原驱动的 CD8 TIL 凋亡是有效自发抗肿瘤免疫的障碍，应被视为癌症免疫疗法发展的关键因素。
