Cancer Cell-Intrinsic Expression of MHC Class II Regulates the Immune Microenvironment and Response to Anti-PD-1 Therapy in Lung Adenocarcinoma

J Immunol. 2020 Apr 15;204(8):2295-2307. doi: 10.4049/jimmunol.1900778. Epub 2020 Mar 16.


MHC class II (MHCII) expression is usually restricted to APC but can be expressed by cancer cells. We examined the effect of cancer cell-specific MHCII (csMHCII) expression in lung adenocarcinoma on T cell recruitment to tumors and response to anti-PD-1 therapy using two orthotopic immunocompetent murine models of non-small cell lung cancer: CMT167 (CMT) and Lewis lung carcinoma (LLC). We previously showed that CMT167 tumors are eradicated by anti-PD1 therapy, whereas LLC tumors are resistant. RNA sequencing analysis of cancer cells recovered from tumors revealed that csMHCII correlated with response to anti-PD1 therapy, with immunotherapy-sensitive CMT167 cells being csMHCII positive, whereas resistant LLC cells were csMHCII negative. To test the functional effects of csMHCII, MHCII expression was altered on the cancer cells through loss- and gain-of-function of CIITA, a master regulator of the MHCII pathway. Loss of CIITA in CMT167 decreased csMHCII and converted tumors from anti-PD-1 sensitive to anti-PD-1 resistant. This was associated with lower levels of Th1 cytokines, decreased T cell infiltration, increased B cell numbers, and decreased macrophage recruitment. Conversely, overexpression of CIITA in LLC cells resulted in csMHCII in vitro and in vivo. Enforced expression of CIITA increased T cell infiltration and sensitized tumors to anti-PD-1 therapy. csMHCII expression was also examined in a subset of surgically resected human lung adenocarcinomas by multispectral imaging, which provided a survival benefit and positively correlated with T cell infiltration. These studies demonstrate a functional role for csMHCII in regulating T cell infiltration and sensitivity to anti-PD-1.

Publication types

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

MeSH terms

  • Adenocarcinoma of Lung / immunology
  • Adenocarcinoma of Lung / therapy*
  • Animals
  • Disease Models, Animal
  • Histocompatibility Antigens Class II / genetics*
  • Histocompatibility Antigens Class II / immunology
  • Lung Neoplasms / immunology
  • Lung Neoplasms / therapy*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / immunology
  • Programmed Cell Death 1 Receptor / immunology
  • Trans-Activators / genetics*
  • Trans-Activators / immunology
  • Tumor Microenvironment / genetics*
  • Tumor Microenvironment / immunology


  • Histocompatibility Antigens Class II
  • MHC class II transactivator protein
  • Nuclear Proteins
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Trans-Activators