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Immunity. 2016 Aug 16;45(2):389-401. doi: 10.1016/j.immuni.2016.07.011. Epub 2016 Aug 9.

Tumor-Specific T Cell Dysfunction Is a Dynamic Antigen-Driven Differentiation Program Initiated Early during Tumorigenesis.

Author information

1
Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Immunology, University of Washington, Seattle, WA 98109, USA; Program of Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. Electronic address: schietia@mskcc.org.
2
Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Division of Hematology, University of Washington, Seattle, WA 98195, USA.
3
Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Immunology, University of Washington, Seattle, WA 98109, USA.
4
Department of Immunology, University of Washington, Seattle, WA 98109, USA.
5
Genomics and Bioinformatics Shared Resources, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
6
Aduro BioTech, Inc., Berkeley, CA 94710, USA.
7
Comparative Medicine Shared Resource, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
8
Divisions of Cellular and Molecular Immunology, DKFZ, 69120 Heidelberg, Germany.
9
Department of Microbiology & Immunology, Penn State Hershey College of Medicine, Hershey, PA 17033, USA.
10
Divisions of Cellular and Molecular Immunology, DKFZ, 69120 Heidelberg, Germany; Institutes of Molecular Medicine and Experimental Immunology, University of Bonn, 53127 Bonn, Germany.
11
Department of Immunology, University of Washington, Seattle, WA 98109, USA; Program of Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. Electronic address: pgreen@uw.edu.

Abstract

CD8(+) T cells recognizing tumor-specific antigens are detected in cancer patients but are dysfunctional. Here we developed a tamoxifen-inducible liver cancer mouse model with a defined oncogenic driver antigen (SV40 large T-antigen) to follow the activation and differentiation of naive tumor-specific CD8(+) T (TST) cells after tumor initiation. Early during the pre-malignant phase of tumorigenesis, TST cells became dysfunctional, exhibiting phenotypic, functional, and transcriptional features similar to dysfunctional T cells isolated from late-stage human tumors. Thus, T cell dysfunction seen in advanced human cancers may already be established early during tumorigenesis. Although the TST cell dysfunctional state was initially therapeutically reversible, it ultimately evolved into a fixed state. Persistent antigen exposure rather than factors associated with the tumor microenvironment drove dysfunction. Moreover, the TST cell differentiation and dysfunction program exhibited features distinct from T cell exhaustion in chronic infections. Strategies to overcome this antigen-driven, cell-intrinsic dysfunction may be required to improve cancer immunotherapy.

PMID:
27521269
PMCID:
PMC5119632
DOI:
10.1016/j.immuni.2016.07.011
[Indexed for MEDLINE]
Free PMC Article

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