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Cancer Immunol Res. 2018 Jan;6(1):14-24. doi: 10.1158/2326-6066.CIR-17-0249. Epub 2017 Nov 2.

Intratumoral CD8+ T-cell Apoptosis Is a Major Component of T-cell Dysfunction and Impedes Antitumor Immunity.

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Department of Pathology, University of Chicago, Chicago, Illinois.
The Committee on Immunology, University of Chicago, Chicago, Illinois.
Department of Pathology, University of Chicago, Chicago, Illinois.
Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, Illinois.


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 in situ 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-xL 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. Cancer Immunol Res; 6(1); 14-24. ©2017 AACR.

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