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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 3

MHC-II+ breast tumors recruit CD4+ T cells and are associated with Lag-3+ TILs.

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MHC-II+ breast tumors recruit CD4+ T cells and are associated with Lag-3...
(A) Representative positive control for Lag-3 IHC in human tonsil. Scale bar: 50 μm. (B) Representative Lag-3+ breast cancer TILs by IHC. Arrows indicate Lag-3+ TILs. Scale bar: 50 μm. (C) Representative AQUA immunofluorescence image of a HLA-DR+ breast tumor case. Scale bar: 100 μm. (D) Difference in tumor-specific HLA-DR expression among LAG-3+ and LAG-3– infiltrated triple-negative breast cancers in all patients (n = 86; left) and only those patients with a percentage of stromal TILs >20% (n = 31; right). ***P < 0.001, 2-tailed t test. (E) CD4 and CD8 and the difference between CD4 and CD8 infiltration in HLA-DR–high (HI) and HLA-DR–low (LO) expressing tumors. **P < 0.01, 2-tailed t test. (F) Association of stromal (noncytokeratin+) PD-L1 expression with HLA-DR expression. **P < 0.01, 2-tailed t test.

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