180 Background: Anti-PD-1 therapy is effective in many cancers, but tumor-intrinsic factors governing response and resistance are largely unknown. MHC-II (HLA-DR) expression on tumor cells can predict response to anti-PD-1. Thus, we sought to determine the molecular features of MHC-II+ tumors in the evolution of anti-PD-1 response. Methods: We performed RNA-seq on 58 anti-PD-1 treated melanoma and lung tumors, including a subset of matched specimens prior to treatment and at acquired resistance. We performed immunohistochemistry (IHC) for immunologic markers, including HLA-DR on tumor cells. In triple-negative breast cancers (TNBC; n = 103), we performed IHC and/or quantitative immunofluorescence (QIF) for LAG3, PD-L1, CD4, CD8, Fc-receptor-like 6 (FCRL6), and granzyme B (GZMB). QIF images were assessed by Automated Quantitative Analysis (AQUA). To determine the functional effect of MHC-II on tumor cells, we generated isogenic MHC-II+ mouse tumors and assessed immune responsiveness and efficacy of checkpoint inhibition. Results: We identified unique inflammatory signatures in HLA-DR+ tumors, correlating with enhanced pre-treatment CD4+ and CD8+ tumor-infiltrating lymphocytes (TILs) and response to anti-PD-1. LAG3+ and FCRL6+ TILs were enriched in HLA-DR+ tumors. LAG3 and FCRL6, known inhibitory receptors which bind MHC-II, were elevated at anti-PD-1 resistance. Similarly, in > 100 TNBCs, HLA-DR+ tumor cells associated with increased CD4+ and CD8+ TILs and enhanced LAG3+ and FCRL6+ TILs. Further, presence of MHC-II-suppressing (LAG3+/FCRL6+) TILs associated with decreased GZMB+ CD8+ T cells, suggesting suppressed cytotoxicity. In mice, enforced expression of MHC-II on tumor cells enhanced CD4-enhanced anti-tumor immunity but was thwarted by LAG3+ TIL recruitment. Combined anti-LAG3 and anti-PD-1 therapy was selectively effective in MHC-II+ tumors. Conclusions: MHC-II+ tumors are immunologically active and may circumvent anti-tumor immunity by targeting MHC-II antigen presentation via recruitment of MHC-II-suppressing TILs. MHC-II expression may be useful to stratify patients to anti-PD-1/anti-LAG3 and eventually, anti-PD-1/anti-FCRL6 combinations.