biostudies-literatureShi HUniversity of Texas Southwestern Medical CenterNIAID NIH HHSNCI NIH HHSNational Institutes of HealthNIH HHSe20240797https://www.ebi.ac.uk/biostudies/studies/S-EPMC11528124biostudies-literatureUnknown221(12)Immune checkpoint inhibitors interfere with T cell exhaustion but often fail to cure or control cancer long-term in patients. Using a genetic screen in C57BL/6J mice, we discovered a mutation in host H2-Aa that caused strong immune-mediated resistance to mouse melanomas. H2-Aa encodes an MHC class II α chain, and its absence in C57BL/6J mice eliminates all MHC-II expression. H2-Aa deficiency, specifically in dendritic cells (DC), led to a quantitative increase in type 2 conventional DC (cDC2) and a decrease in cDC1. H2-Aa-deficient cDC2, but not cDC1, were essential for melanoma suppression and effectively cross-primed and recruited CD8 T cells into tumors. Lack of T regulatory cells, also observed in H2-Aa deficiency, contributed to melanoma suppression. Acute disruption of H2-Aa was therapeutic in melanoma-bearing mice, particularly when combined with checkpoint inhibition, which had no therapeutic effect by itself. Our findings suggest that inhibiting MHC-II may be an effective immunotherapeutic approach to enhance immune responses to cancer.The Journal of experimental medicineSuppression of melanoma by mice lacking MHC-II: Mechanisms and implications for cancer immunotherapy.PMC11528124R01 AI125581AI125581CA258602R01 CA258602Duran Bojorquez CMoresco EMYSchneider SMedler DXing CQuan JWang JLi XBeutler BMoresco JJLudwig SLiu AKumar AShi HBrowning RfalseSuppression of melanoma by mice lacking MHC-II: Mechanisms and implications for cancer immunotherapy.Immune checkpoint inhibitors interfere with T cell exhaustion but often fail to cure or control cancer long-term in patients. Using a genetic screen in C57BL/6J mice, we discovered a mutation in host H2-Aa that caused strong immune-mediated resistance to mouse melanomas. H2-Aa encodes an MHC class II α chain, and its absence in C57BL/6J mice eliminates all MHC-II expression. H2-Aa deficiency, specifically in dendritic cells (DC), led to a quantitative increase in type 2 conventional DC (cDC2) and a decrease in cDC1. H2-Aa-deficient cDC2, but not cDC1, were essential for melanoma suppression and effectively cross-primed and recruited CD8 T cells into tumors. Lack of T regulatory cells, also observed in H2-Aa deficiency, contributed to melanoma suppression. Acute disruption of H2-Aa was therapeutic in melanoma-bearing mice, particularly when combined with checkpoint inhibition, which had no therapeutic effect by itself. Our findings suggest that inhibiting MHC-II may be an effective immunotherapeutic approach to enhance immune responses to cancer.2024-01-01T00:00:00Z2024 Dec2026-07-09T10:53:18.831Z2025-04-06T09:32:07.263ZS-EPMC115281243947060710.1084/jem.20240797