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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 5

Enhanced T cell–recruiting chemokines and Lag3 expression in MHC-II+ murine tumors.

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Enhanced T cell–recruiting chemokines and Lag3 expression in MHC-II+ mur...
(A) Heatmap visualization of altered gene expression levels in nonrejected tumors from Figure 2H. Transcript counts (NanoString PanCancer Immune profiling) were row normalized/standardized for visualization. (B) Gene expression levels of immune checkpoints Pd-1, Tim-3, and Lag-3 in Ciita+ and control tumors (n = 20). (C) Cultured MMTV-neu tumor cells (cell line) expressing Ciita or vector control were analyzed by quantitative real-time PCR for tumor-specific changes in T cell–recruiting chemokines. n = 3 independent experiments. *P < 0.05; **P < 0.01; ***P < 0.001, a 2-tailed t test. (D) NanoString gene expression data from MMTV-neu Ciita+ or vector control tumors (n = 12) harvested at humane endpoints (1.5–2 cm3) were queried for expression levels of T cell–attracting chemokines (see Supplemental Figure 9A fore eomesodermin [Eomes]). *P < 0.05; **P < 0.01, 2-tailed t test.

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