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• W4308381805 abstract "<h3>Background</h3> Stem-like CD8 T cells that are regulated by the transcription factor TCF1 are key players in the response to immune checkpoint blockers (ICB). Recent findings indicate that the dependance on TCF1⁺ stem-like T cells for ICB efficacy may not be equal across patients and in different tumor contexts. <h3>Methods</h3> Here we leveraged TCF1 conditional knock-out (TCF1-cKO) mice to investigate how TCF1 instructs the early fate and functions of CD8 cells upon ICB therapy in tumors that differ for immunogenicity and levels of tumor antigens expression. <h3>Results</h3> Strikingly, we discovered that TCF1 expression in CD8 T cells is required for ICB efficacy in poorly immunogenic B16OVA melanomas but is dispensable in highly immunogenic MC38OVA colorectal tumors. Single-cell-RNA sequencing and immunophenotyping revealed defective priming and expansion of tumor-specific TCF1-cKO T cells in the tumor draining lymph-node (TDLN) of B16OVA- but not MC38OVA-bearing mice treated with ICB. In vitro, we found defective proliferation, reduced PD-1 and CD28 up-regulation and reduced phosphorylation of key molecules downstream the T cell receptor pathway when TCF1 cKO T cells were stimulated with low doses of antigens but not when stimulated with strong TCR signals. These data indicate that TCF1 poises T cells for optimal activation. Furthermore, transcriptional profiling of T cells in the TDLN further revealed the accumulation of a subset of tumor-specific naïve T cells poised to give rise to short-lived effectors in TCF1 cKO mice and thus is less suited to sustain anti-tumor responses in poorly immunogenic tumors where expansion of T cells retaining stem-like potential is required for durable anti-tumor responses. In tumors, single-cell-RNA sequencing and immunophenotyping showed that in MC38OVA tumors both WT and TCF1-cKO mice expanded a CD8 subset sharing a signature with transitory effector cells that mediate ICB efficacy in chronic viral infection models. Conversely, B16-OVA tumors retained a higher frequency of stem-like cells, failed to expand transitory effectors and accumulated Tox+ CD8 T cells, sharing a signature with CD8 cells expanded in non-responders to ICB. Importantly, loss of TCF1 was associated with reduced maintenance and proliferation of stem-like precursors and reduced expression of the Tox gene which was required for the survival of late effectors, altogether contributing to the failure of TCF1-cKO mice to sustain effective ICB responses. <h3>Conclusions</h3> Our study highlights a role for TCF1 in the early stages of the CD8 T cell response with important implications for guiding the choice of optimal therapeutic interventions in tumors expressing low neoantigen levels." @default.
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• W4308381805 date "2022-11-01" @default.
• W4308381805 modified "2023-09-27" @default.
• W4308381805 title "514 Tumor context dictates reliance on TCF1 for response to immunotherapy" @default.
• W4308381805 doi "https://doi.org/10.1136/jitc-2022-sitc2022.0514" @default.
• W4308381805 hasPublicationYear "2022" @default.
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