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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.

Author information

1
Department of Pathology, University of Chicago, Chicago, Illinois.
2
The Committee on Immunology, University of Chicago, Chicago, Illinois.
3
Department of Pathology, University of Chicago, Chicago, Illinois. tgajewsk@medicine.bsd.uchicago.edu.
4
Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, Illinois.

Abstract

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.

PMID:
29097422
PMCID:
PMC5754226
DOI:
10.1158/2326-6066.CIR-17-0249
[Indexed for MEDLINE]
Free PMC Article

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