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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 8

The alternative MHC-II receptor FCRL6 is an inhibitor of T cell and NK cell activity.

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The alternative MHC-II receptor FCRL6 is an inhibitor of T cell and NK c...
(A) NK-92 and K562 transductants were stained with anti-FCRL6 or anti–HLA-DR, respectively. K562 vector (top), K562 DRa+b1 (middle), or K562 CIITA (bottom) transductants were cultured with NK-92 FCRL6 transductants (red lines), NK-92 vector (blue lines), or parental NK-92 cells (black lines) at various effector-to-target (E/T) ratios and assayed for K562 cytotoxicity in 51Cr release assays. Experiments were performed in triplicate; lines represent the mean ± SD. n = 4; P values were calculated using Student’s t test. *P < 0.01, #P < 0.02. (B) Blood mononuclear cells were cultured for 6 days in the presence of the CEF peptide pool with anti-FCRL6, anti–PD-L1, or an isotype-matched control mAb. Cells were collected, restimulated with CEF for 6 hours, and analyzed for intracellular cytokine production by flow cytometry. CD8+ T cells from one representative donor were gated, and the percentages of cells staining positive for the indicated cytokines are shown in the quadrants of each dot plot. (C) Paired data points from healthy donors (n = 12 for IFN-γ; n = 9 for TNF-α) are indicated by lines, and statistical significance was determined using the Wilcoxon signed-rank test.

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