Tbc1d10c is a selective, constitutive suppressor of the CD8 T-cell anti-tumor response.

Autor:	Cohen AO; Department of Dermatology, Columbia University Irving Medical Center, Vagelos College of Physicians & Surgeons, New York, NY 10032, USA., Woo SH; Department of Dermatology, Columbia University Irving Medical Center, Vagelos College of Physicians & Surgeons, New York, NY 10032, USA.; Discovery Biology Division, Velia Therapeutics, San Diego, CA, USA., Zhang J; Department of Dermatology, Columbia University Irving Medical Center, Vagelos College of Physicians & Surgeons, New York, NY 10032, USA., Cho J; Department of Dermatology, Columbia University Irving Medical Center, Vagelos College of Physicians & Surgeons, New York, NY 10032, USA.; Global Safety Assurance, Reckitt Benckiser Inc., Montvale, NJ, USA., Ruiz ME; Department of Dermatology, Columbia University Irving Medical Center, Vagelos College of Physicians & Surgeons, New York, NY 10032, USA.; Olink Proteomics, Los Angeles, CA 90045, USA., Gong J; Department of Dermatology, Columbia University Irving Medical Center, Vagelos College of Physicians & Surgeons, New York, NY 10032, USA.; Processing Cell Sciences, Merck & Co., Inc, Kenilworth, NJ, USA., Du R; Department of Dermatology, Columbia University Irving Medical Center, Vagelos College of Physicians & Surgeons, New York, NY 10032, USA., Yarygina O; Department of Dermatology, Columbia University Irving Medical Center, Vagelos College of Physicians & Surgeons, New York, NY 10032, USA., Jafri DZ; Department of Dermatology, Columbia University Irving Medical Center, Vagelos College of Physicians & Surgeons, New York, NY 10032, USA., Bachelor MA; Department of Dermatology, Columbia University Irving Medical Center, Vagelos College of Physicians & Surgeons, New York, NY 10032, USA.; Boston Scientific, Center for Biological Innovation, Global Preclinical Sciences, Marlborough, MA, USA., Finlayson MO; Department of Systems Biology, Columbia University Irving Medical Center, Vagelos College of Physicians & Surgeons, New York, NY, USA.; Simons Foundation, New York, NY 10010, USA., Soni RK; Proteomics & Macromolecular Crystallography Shared Resource, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA., Hayden MS; Department of Surgery, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA., Owens DM; Department of Dermatology, Columbia University Irving Medical Center, Vagelos College of Physicians & Surgeons, New York, NY 10032, USA.; Department of Pathology & Cell Biology, Columbia University Irving Medical Center, Vagelos College of Physicians & Surgeons, New York, NY, USA.
Jazyk:	angličtina
Zdroj:	Oncoimmunology [Oncoimmunology] 2022 Nov 02; Vol. 11 (1), pp. 2141011. Date of Electronic Publication: 2022 Nov 02 (Print Publication: 2022).
DOI:	10.1080/2162402X.2022.2141011
Abstrakt:	Cancer immunotherapy approaches target signaling pathways that are highly synonymous between CD4 and CD8 T-cell subsets and, therefore, often stimulate nonspecific lymphocyte activation, resulting in cytotoxicity to otherwise healthy tissue. The goal of our study was to identify intrinsic modulators of basic T lymphocyte activation pathways that could discriminately bolster CD8 anti-tumor effector responses. Using a Tbc1d10c null mouse, we observed marked resistance to a range of tumor types conferred by Tbc1d10c deficiency. Moreover, tumor-bearing Tbc1d10c null mice receiving PD-1 or CTLA-4 monotherapy exhibited a 33% or 90% cure rate, respectively. While Tbc1d10c was not expressed in solid tumor cells, Tbc1d10c disruption selectively augmented CD8 T-cell activation and cytotoxic effector responses and adoptive transfer of CD8 T cells alone was sufficient to recapitulate Tbc1d10c null tumor resistance. Mechanistically, Tbc1d10c suppressed CD8 T-cell activation and anti-tumor function by intersecting canonical NF-κB pathway activation via regulation of Map3k3-mediated IKKβ phosphorylation. Strikingly, none of these cellular or molecular perturbations in the NF-κB pathway were featured in Tbc1d10c null CD4 T cells. Our findings identify a Tbc1d10c-Map3k3-NF-κB signaling axis as a viable therapeutic target to promote CD8 T-cell anti-tumor immunity while circumventing CD4 T cell-associated cytotoxicity and NF-κB activation in tumor cells. Competing Interests: No potential conflict of interest was reported by the author(s). (© 2022 The Author(s). Published with license by Taylor & Francis Group, LLC.)
Databáze:	MEDLINE
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