期刊
SCIENCE ADVANCES
卷 6, 期 27, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.aaz7809
关键词
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资金
- Swiss Government Excellence Scholarship
- NIH [R01CA174385]
- CPRIT [RP180466]
- MRA award [509800]
- Owens Foundation, CDMRP [CA160591]
- NSF [1705464]
- Swiss National Science Foundation (SNSF) [31003A_182470]
- Swiss Institute for Experimental Cancer Research [ISREC 26075483]
- European Research Council [802773]
- Cancer Research Institute Clinic and Laboratory Integration Program
- SNSF [31003A_173156]
- Leukemia & Lymphoma Society (LLS) Translational Research Program grant [6490-16]
- CPRIT Individual Investigator Research Award [RP160345]
- Swiss Cancer Research grant [KFS-4542-08-2018-R]
- Department of Oncology, Lausanne University Hospital
- Ludwig Institute for Cancer Research
- University of Lausanne
- Dan L. Duncan Comprehensive Cancer Center support grant [P30CA125123]
Transgenic coexpression of a class I-restricted tumor antigen-specific T cell receptor (TCR) and CD8 alpha beta (TCR8) redirects antigen specificity of CD4(+) T cells. Reinforcement of biophysical properties and early TCR signaling explain how redirected CD4(+) T cells recognize target cells, but the transcriptional basis for their acquired antitumor function remains elusive. We, therefore, interrogated redirected human CD4(+) and CD8(+) T cells by single-cell RNA sequencing and characterized them experimentally in bulk and single-cell assays and a mouse xenograft model. TCR8 expression enhanced CD8(+) T cell function and preserved less differentiated CD4(+) and CD8(+) T cells after tumor challenge. TCR8(+) CD4(+) T cells were most potent by activating multiple transcriptional programs associated with enhanced antitumor function. We found sustained activation of cytotoxicity, costimulation, oxidative phosphorylation- and proliferation-related genes, and simultaneously reduced differentiation and exhaustion. Our study identifies molecular features of TCR8 expression that can guide the development of enhanced immunotherapies.
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