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.
This work was supported by the National Cancer Institute, National Institutes of Health (NIH) (R01 CA162226 and P50 CA058187) and by Golfers against Cancer. The University of Colorado Cancer Center Flow Cytometry and the Genomics and Microarray Shared Resources are supported by NIH P30CA046934. The University of Colorado Cancer Center Flow Cytometry Core Facility is funded through a support grant from the National Cancer Institute (P30 CA046934). A.M.J. was supported by NIH National Research Service Award T32 CA174648-01. Imaging experiments were performed in the University of Colorado Anschutz Medical Campus Advanced Light Microscopy Core, supported in part by NIH/National Center for Advancing Translational Sciences and Colorado Clinical and Translational Sciences Institute Grant UL1 TR001082. This work was also supported by the LUNGevity Foundation (2018-03).
The online version of this article contains supplemental material.
Abbreviations used in this article:
- cancer cell–specific MHCII
- high-power field
- Lewis lung carcinoma
- MHC class I
- MHC class II
- non–small cell lung cancer
- nontargeting control
- programmed cell death protein-1
- programmed cell death ligand-1
- quantitative real-time PCR
- RNA sequencing
- shRNA targeting CIITA
- short hairpin RNA
- tumor microenvironment.
- Received July 9, 2019.
- Accepted February 7, 2020.
- Copyright © 2020 by The American Association of Immunologists, Inc.