title: Checkpoint blockade immunotherapy relies on T-bet but not Eomes to induce effector function in tumor-infiltrating CD8+ T cells.
abstract: Coinhibitory receptor blockade is a promising strategy to boost T-cell immunity against a variety of human cancers. However, many patients still do not benefit from this treatment, and responders often experience immune-related toxicities. These issues highlight the need for advanced mechanistic understanding to improve patient outcomes and uncover clinically relevant biomarkers of treatment efficacy. However, the T-cell-intrinsic signaling pathways engaged during checkpoint blockade treatment are not well defined, particularly for combination approaches. Using a murine model to study how effector CD8(+) T-cell responses to tumors may be enhanced in a tolerizing environment, we identified a critical role for the T-box transcription factor T-bet. Combination blockade of CTLA-4, PD-1, and LAG-3 induced T-bet expression in responding tumor/self-reactive CD8(+) T cells. Eradication of established leukemia using this immunotherapy regimen depended on T-bet induction, which was required for IFNγ production and cytotoxicity by tumor-infiltrating T cells, and for efficient trafficking to disseminated tumor sites. These data provide new insight into the success of checkpoint blockade for cancer immunotherapy, revealing T-bet as a key transcriptional regulator of tumor-reactive CD8(+) T-cell effector differentiation under otherwise tolerizing conditions.
authors.affiliation: Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri.
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Berrien-Elliott
authors.affiliation: Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri.
authors.forename: Jinyun
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri.
authors.forename: Lauryn E
authors.initials: LE
authors.lastname: Swier
authors.affiliation: Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri.
authors.forename: Stephanie R
authors.initials: SR
authors.lastname: Jackson
authors.affiliation: Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri.
authors.forename: Collin L
authors.initials: CL
authors.lastname: Chen
authors.affiliation: Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri. Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, Missouri.
authors.forename: Maureen J
authors.initials: MJ
authors.lastname: Donlin
authors.affiliation: Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri. Saint Louis University Cancer Center, St. Louis, Missouri. rteague@slu.edu.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Teague
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology; D007167:Immunotherapy / Q000379:methods*; D007942:Leukemia, Experimental / Q000235:genetics / Q000276:immunology / Q000628:therapy; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D020825:T-Box Domain Proteins / Q000276:immunology*; D000098815:T-bet Transcription Factor
chemical_list: C491198:Eomes protein, mouse; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor