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

JCI Insight. 2018 Dec 20;3(24):e120360. doi: 10.1172/jci.insight.120360.

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.

Keywords: Adaptive immunity; Antigen presentation; Cancer immunotherapy; Oncology; Therapeutics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adaptive Immunity
  • Animals
  • Antibodies, Neutralizing
  • Antigens, CD / metabolism*
  • Breast Neoplasms / metabolism
  • CD4-Positive T-Lymphocytes
  • Cell Line, Tumor
  • HLA-DR Antigens / metabolism
  • Histocompatibility Antigens Class II / genetics
  • Histocompatibility Antigens Class II / immunology*
  • Histocompatibility Antigens Class II / metabolism*
  • Humans
  • Immunotherapy*
  • Killer Cells, Natural / immunology
  • Ligands
  • Mice
  • Programmed Cell Death 1 Receptor / metabolism
  • Receptors, Antigen, T-Cell
  • Receptors, Cell Surface / metabolism*
  • T-Lymphocytes / immunology
  • Tumor Microenvironment

Substances

  • Antibodies, Neutralizing
  • Antigens, CD
  • CD223 antigen
  • FCRL6 protein, human
  • HLA-DR Antigens
  • Histocompatibility Antigens Class II
  • Ligands
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Receptors, Antigen, T-Cell
  • Receptors, Cell Surface