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Tumor-specific MHC-II expression drives a unique pattern of resistance to immunotherapy via LAG-3/FCRL6 engagement
Douglas B. Johnson, … , Randall S. Davis, Justin M. Balko
Douglas B. Johnson, … , Randall S. Davis, Justin M. Balko
Published December 20, 2018
Citation Information: JCI Insight. 2018;3(24):e120360. https://doi.org/10.1172/jci.insight.120360.
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Research Article Oncology Therapeutics

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

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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 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.

Authors

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 Jr., Yaomin Xu, Jeffrey A. Sosman, Randall S. Davis, Justin M. Balko

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Figure 9

The alternative MHC-II receptor FCRL6 is enriched in MHC-II+ tumors and is associated with acquired resistance to anti–PD-1.

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The alternative MHC-II receptor FCRL6 is enriched in MHC-II+ tumors and ...
(A) mRNA expression from RNA-sequencing data for FCRL3 and FCRL6 in MHC-II+ and MHC-II– melanoma and lung cancers. (B) mRNA expression from RNA-sequencing data for FCRL3 and FCRL6 in untreated and postprogression/relapse specimens. (C) Quantification of IHC for FCRL6+ TILs in pairs of melanomas before and after resistance to anti–PD-1 therapy. (D) MHC-II/HLA-DR AQUA scores in triple-negative breast cancers stratified by the presence or absence of FCRL6+ lymphocytes. (E) Coexpression of Lag-3 and FCRL6 on TILs in postneoadjuvant triple-negative breast cancers. (F) MHC-II/HLA-DR AQUA scores in triple-negative breast cancers stratified by the presence or absence of FCRL6+ lymphocytes and Lag-3+ lymphocytes. (G) Fraction of CD8+ lymphocytes expressing granzyme B (AQUA), stratified by the presence or absence of FCRL6+ lymphocytes (IHC), Lag-3+ lymphocytes (IHC), or total tumor microenvironment PD-L1 expression (AQUA). *P < 0.05 by Mann Whitney U test.

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