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JCI Insight. 2018 Dec 20;3(24). pii: 120360. doi: 10.1172/jci.insight.120360.

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

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Department of Medicine and.
Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Department of Pathology, University of California, San Diego, San Diego, California, USA.
Department of Pathology Microbiology, and Immunology, and.
Breast Cancer Research Program, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Department of Pathology, GZA-ZNA Hospitals, Antwerp, Belgium.
Department of Oncology, University of Melbourne and Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
Clearview Cancer Institute, Huntsville, Alabama, USA.
Departments of Pathology and Medicine, Yale University, New Haven, Connecticut, USA.
Navigate BioPharma Services Inc., a Novartis Company, Carlsbad, California, USA.
Department of Medicine, Northwestern University, Chicago, Illinois, USA.
Departments of Medicine, Microbiology, and Biochemistry and Molecular Genetics, University of Alabama, Birmingham, Alabama, USA.


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.


Adaptive immunity; Antigen presentation; Cancer immunotherapy; Oncology; Therapeutics

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