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

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 1

MHC-II/HLA-DR expression in patient tumor samples is associated with unique patterns of inflammation and enhanced CD4, CD8, and LAG-3+ infiltrate.

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MHC-II/HLA-DR expression in patient tumor samples is associated with uni...
(A) Representative images of IHC from HLA-DR+ and HLA-DR– tumors. HLA-DR is stained in brown (DAB), and Sox10, a nuclear melanoma marker, is stained in pink (Mach Red). Scale bar: 50 μm. (B) Gene set analysis from RNA-sequencing analysis of IHC-defined tumor HLA-DR+ (≥5% tumor cells) or HLA-DR– (<5% tumor cells) melanoma and lung specimens. After significant (FDR < 10%) gene set scores were defined, scores were created as the mean of all genes in each signature for each sample and plotted as row-standardized Z-scores with heatmap representation. (C) Overlap of enriched gene sets in MHC-II+ tumors versus melanoma cell lines (ref. 12). (D) Pearson’s correlation matrix of gene expression associations between immune response and inhibitory markers among PD-1–treated patient samples from melanoma and lung cancer (n = 50). Data represent correlation among TPM RNA-sequencing values, except “HLA-DR_TUMOR,” which is the correlation with tumor HLA-DR percent positivity by IHC (n = 41 of 50 available data points). Values in the individual boxes represent the Pearson’s correlation coefficient.