biostudies-literatureLiu HJLAM FoundationEngles Family TSC/LAM Research Fund Lee Family Research FundNHLBI NIH HHSU.S. Department of DefenseU.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood InstituteNIAMS NIH HHS1214https://www.ebi.ac.uk/biostudies/studies/S-EPMC9984496biostudies-literatureUnknown14(1)Identifying the mechanisms underlying the regulation of immune checkpoint molecules and the therapeutic impact of targeting them in cancer is critical. Here we show that high expression of the immune checkpoint B7-H3 (CD276) and high mTORC1 activity correlate with immunosuppressive phenotypes and worse clinical outcomes in 11,060 TCGA human tumors. We find that mTORC1 upregulates B7-H3 expression via direct phosphorylation of the transcription factor YY2 by p70 S6 kinase. Inhibition of B7-H3 suppresses mTORC1-hyperactive tumor growth via an immune-mediated mechanism involving increased T-cell activity and IFN-γ responses coupled with increased tumor cell expression of MHC-II. CITE-seq reveals strikingly increased cytotoxic CD38⁺CD39⁺CD4⁺ T cells in B7-H3-deNature communicationsmTORC1 upregulates B7-H3/CD276 to inhibit antitumor T cells and drive tumor immune evasion.PMC9984496K08 AR077037U01 HL1310221U01HL131022-01W81XWH-21-1-0223LAM0149C01-21Zarei MFreeman GJLiu HJKhabibullin DDu HKwiatkowski DJHenske EPWei KfalsemTORC1 upregulates B7-H3/CD276 to inhibit antitumor T cells and drive tumor immune evasion.Identifying the mechanisms underlying the regulation of immune checkpoint molecules and the therapeutic impact of targeting them in cancer is critical. Here we show that high expression of the immune checkpoint B7-H3 (CD276) and high mTORC1 activity correlate with immunosuppressive phenotypes and worse clinical outcomes in 11,060 TCGA human tumors. We find that mTORC1 upregulates B7-H3 expression via direct phosphorylation of the transcription factor YY2 by p70 S6 kinase. Inhibition of B7-H3 suppresses mTORC1-hyperactive tumor growth via an immune-mediated mechanism involving increased T-cell activity and IFN-γ responses coupled with increased tumor cell expression of MHC-II. CITE-seq reveals strikingly increased cytotoxic CD38⁺CD39⁺CD4⁺ T cells in B7-H3-de2023-01-01T00:00:00Z2023 Mar2025-04-04T11:35:40.149Z2025-04-04T11:35:40.149ZS-EPMC99844963686904810.1038/s41467-023-36881-7