期刊
ONCOIMMUNOLOGY
卷 11, 期 1, 页码 -出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/2162402X.2022.2141011
关键词
Immuno-oncology; squamous cell carcinoma; melanoma; carabin; NF-kappa B; Map3k3
资金
- NCI [5P30CA013696-44]
- NIH [S10RR027050, S10OD020056, R01CA114014, F32AR055007, P30AR069632]
- NYDOH [DOH01-C32582GG]
- Cancer Research Institute CLIP Award
This study identifies the Tbc1d10c-Map3k3-NF-kappa B signaling axis as a viable therapeutic target to enhance CD8 T-cell anti-tumor immunity while avoiding CD4 T cell-associated cytotoxicity and NF-kappa B activation in tumor cells.
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-kappa B pathway activation via regulation of Map3k3-mediated IKK beta phosphorylation. Strikingly, none of these cellular or molecular perturbations in the NF-kappa B pathway were featured in Tbc1d10c null CD4 T cells. Our findings identify a Tbc1d10c-Map3k3-NF-kappa B signaling axis as a viable therapeutic target to promote CD8 T-cell anti-tumor immunity while circumventing CD4 T cell-associated cytotoxicity and NF-kappa B activation in tumor cells.
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