Journal article
Tumor-specific MHC-II expression drives a unique pattern of resistance to immunotherapy via LAG-3/FCRL6 engagement
DB Johnson, MJ Nixon, Y Wang, DY Wang, E Castellanos, MV Estrada, PI Ericsson-Gonzalez, CH Cote, R Salgado, V Sanchez, PT Dean, SR Opalenik, DM Schreeder, DL Rimm, JY Kim, J Bordeaux, S Loi, L Horn, ME Sanders, PB Ferrell Show all
Jci Insight | Published : 2018
Abstract
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..
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Awarded by National Heart, Lung, and Blood Institute
Funding Acknowledgements
Funding for this work was provided by the Vanderbilt-Incyte Research Alliance Program Grant (to JMB, DBJ, and YX) as well as the Department of Defense Era of Hope Scholar Award (BC170037 to JMB); NIH grants R00CA181491 (to JMB), K23CA204726 (to DBJ), and R21AI097729 (to RSD); the James C. Bradford Jr. Melanoma Fund (to DBJ); the Susan G. Komen for the Cure Foundation (CCR14299052 to JMB); the Breast Cancer Specialized Program of Research Excellence (SPORE P50 CA098131); a Vanderbilt-Ingram Cancer Center Support Grant (P30 CA68485); and the University of Alabama at Birmingham Center For AIDS Research (P30 AI027767).