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Immunotherapies targeting the PD-1 pathway produce durable responses in many cancers, but the tumor-intrinsic factors governing response and resistance are largely unknown. MHC-II expression on tumor cells can predict response to anti-PD-1 therapy. We therefore sought to determine how MHC-II expression by tumor cells promotes PD-1 dependency. Using transcriptional profiling of anti-PD-1-treated patients, we identified unique patterns of immune activation in MHC-II+ tumors. In patients and preclinical models, MHC-II+ tumors recruited CD4+ T cells and developed dependency on PD-1 as well as Lag-3 (an MHC-II inhibitory receptor), which was upregulated in MHC-II+ tumors at acquired resistance to anti-PD-1. Finally, we identify enhanced expression of FCRL6, another MHC-II receptor expressed on NK and T cells, in the microenvironment of MHC-II+ tumors. We ascribe this to what we believe to be a novel inhibitory function of FCRL6 engagement, identifying it as an immunotherapy target. These data suggest a MHC-II-mediated context-dependent mechanism of adaptive resistance to PD-1-targeting immunotherapy.


Douglas B Johnson, Mellissa J Nixon, Yu Wang, Daniel Y Wang, Emily Castellanos, Monica V Estrada, Paula I Ericsson-Gonzalez, Candace H Cote, Roberto Salgado, Violeta Sanchez, Phillip T Dean, Susan R Opalenik, Daniel M Schreeder, David L Rimm, Ju Young Kim, Jennifer Bordeaux, Sherene Loi, Leora Horn, Melinda E Sanders, P Brent Ferrell, Yaomin Xu, Jeffrey A Sosman, Randall S Davis, Justin M Balko. Tumor-specific MHC-II expression drives a unique pattern of resistance to immunotherapy via LAG-3/FCRL6 engagement. JCI insight. 2018 Dec 20;3(24)

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PMID: 30568030

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