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

Authors :
Johnson, Amber M.
Bullock, Bonnie L.
Neuwelt, Alexander J.
Poczobutt, Joanna M.
Kaspar, Rachael E.
Li, Howard Y.
Kwak, Jeff W.
Hopp, Katharina
Weiser-Evans, Mary C. M.
Heasley, Lynn E.
Schenk, Erin L.
Clambey, Eric T.
Nemenoff, Raphael A.
Source :
Journal of Immunology. 4/15/2020, Vol. 204 Issue 8, p2295-2307. 13p.
Publication Year :
2020

Abstract

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-offunction 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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00221767
Volume :
204
Issue :
8
Database :
Academic Search Index
Journal :
Journal of Immunology
Publication Type :
Academic Journal
Accession number :
157096188
Full Text :
https://doi.org/10.4049/jimmunol.1900778