title: Tumor-Specific T Cell Dysfunction Is a Dynamic Antigen-Driven Differentiation Program Initiated Early during Tumorigenesis.
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.
authors: 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.
authors: Andrea
authors: A
authors: Schietinger
authors: Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Division of Hematology, University of Washington, Seattle, WA 98195, USA.
authors: Mary
authors: M
authors: Philip
authors: Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Immunology, University of Washington, Seattle, WA 98109, USA.
authors: Varintra E
authors: VE
authors: Krisnawan
authors: Department of Immunology, University of Washington, Seattle, WA 98109, USA.
authors: Edison Y
authors: EY
authors: Chiu
authors: Genomics and Bioinformatics Shared Resources, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors: Jeffrey J
authors: JJ
authors: Delrow
authors: Genomics and Bioinformatics Shared Resources, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors: Ryan S
authors: RS
authors: Basom
authors: Aduro BioTech, Inc., Berkeley, CA 94710, USA.
authors: Peter
authors: P
authors: Lauer
authors: Aduro BioTech, Inc., Berkeley, CA 94710, USA.
authors: Dirk G
authors: DG
authors: Brockstedt
authors: Comparative Medicine Shared Resource, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors: Sue E
authors: SE
authors: Knoblaugh
authors: Divisions of Cellular and Molecular Immunology, DKFZ, 69120 Heidelberg, Germany.
authors: Günter J
authors: GJ
authors: Hämmerling
authors: Department of Microbiology & Immunology, Penn State Hershey College of Medicine, Hershey, PA 17033, USA.
authors: Todd D
authors: TD
authors: Schell
authors: Divisions of Cellular and Molecular Immunology, DKFZ, 69120 Heidelberg, Germany; Institutes of Molecular Medicine and Experimental Immunology, University of Bonn, 53127 Bonn, Germany.
authors: Natalio
authors: N
authors: Garbi
authors: 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.
authors: Philip D
authors: PD
authors: Greenberg
mesh_terms: D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology*; D063646:Carcinogenesis; D002454:Cell Differentiation; D002478:Cells, Cultured; D016922:Cellular Senescence; D004195:Disease Models, Animal; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008113:Liver Neoplasms / Q000139:chemically induced / Q000276:immunology* / Q000628:therapy; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013629:Tamoxifen; D059016:Tumor Microenvironment
chemical_list: D000952:Antigens, Polyomavirus Transforming; D019496:Cancer Vaccines; D013629:Tamoxifen