Melanoma-specific MHC-II expression represents a tumour-autonomous phenotype and predicts response to anti-PD-1/PD-L1 therapy
Douglas B Johnson, Monica V Estrada, Roberto Salgado, Violeta Sanchez, Deon B Doxie, Susan R Opalenik, Anna E Vilgelm, Emily Feld, Adam S Johnson, Allison R Greenplate, Melinda E Sanders, Christine M Lovly, Dennie T Frederick, Mark C Kelley, Ann Richmond, Jonathan M Irish, Yu Shyr, Ryan J Sullivan, Igor Puzanov, Jeffrey A Sosman, Justin M Balko, Douglas B Johnson, Monica V Estrada, Roberto Salgado, Violeta Sanchez, Deon B Doxie, Susan R Opalenik, Anna E Vilgelm, Emily Feld, Adam S Johnson, Allison R Greenplate, Melinda E Sanders, Christine M Lovly, Dennie T Frederick, Mark C Kelley, Ann Richmond, Jonathan M Irish, Yu Shyr, Ryan J Sullivan, Igor Puzanov, Jeffrey A Sosman, Justin M Balko
Abstract
Anti-PD-1 therapy yields objective clinical responses in 30-40% of advanced melanoma patients. Since most patients do not respond, predictive biomarkers to guide treatment selection are needed. We hypothesize that MHC-I/II expression is required for tumour antigen presentation and may predict anti-PD-1 therapy response. In this study, across 60 melanoma cell lines, we find bimodal expression patterns of MHC-II, while MHC-I expression was ubiquitous. A unique subset of melanomas are capable of expressing MHC-II under basal or IFNγ-stimulated conditions. Using pathway analysis, we show that MHC-II(+) cell lines demonstrate signatures of 'PD-1 signalling', 'allograft rejection' and 'T-cell receptor signalling', among others. In two independent cohorts of anti-PD-1-treated melanoma patients, MHC-II positivity on tumour cells is associated with therapeutic response, progression-free and overall survival, as well as CD4(+) and CD8(+) tumour infiltrate. MHC-II(+) tumours can be identified by melanoma-specific immunohistochemistry using commercially available antibodies for HLA-DR to improve anti-PD-1 patient selection.
Conflict of interest statement
D.B.J., J.M.B., V.S. and M.E.S. have filed provisionary patent on use of MHC-II to predict response to immunotherapy. The remaining authors declare no competing financial interests.
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