Journal article

Tumor-specific MHC-II expression drives a unique pattern of resistance to immunotherapy via LAG-3/FCRL6 engagement

Douglas B Johnson, Mellissa J Nixon, Yu Wang, Daniel Y Wang, Emily Castellanos, Monica Estrada, Paula 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 Show all

JCI INSIGHT | AMER SOC CLINICAL INVESTIGATION INC | 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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Grants

Awarded by Department of Defense Era of Hope Scholar Award


Awarded by NIH


Awarded by Susan G. Komen for the Cure Foundation


Awarded by Breast Cancer Specialized Program of Research Excellence


Awarded by Vanderbilt-Ingram Cancer Center Support Grant


Awarded by University of Alabama at Birmingham Center For AIDS Research


Awarded by NATIONAL CANCER INSTITUTE


Awarded by NATIONAL HEART, LUNG, AND BLOOD INSTITUTE


Awarded by NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES


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).