PMID- 32179637 OWN - NLM STAT- MEDLINE DCOM- 20201230 LR - 20210611 IS - 1550-6606 (Electronic) IS - 0022-1767 (Print) IS - 0022-1767 (Linking) VI - 204 IP - 8 DP - 2020 Apr 15 TI - Cancer Cell-Intrinsic Expression of MHC Class II Regulates the Immune Microenvironment and Response to Anti-PD-1 Therapy in Lung Adenocarcinoma. PG - 2295-2307 LID - 10.4049/jimmunol.1900778 [doi] AB - 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. CI - Copyright (c) 2020 by The American Association of Immunologists, Inc. FAU - Johnson, Amber M AU - Johnson AM AUID- ORCID: 0000-0002-5392-8705 AD - Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045. FAU - Bullock, Bonnie L AU - Bullock BL AD - Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045. FAU - Neuwelt, Alexander J AU - Neuwelt AJ AD - Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045. FAU - Poczobutt, Joanna M AU - Poczobutt JM AD - Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045. FAU - Kaspar, Rachael E AU - Kaspar RE AUID- ORCID: 0000-0002-1181-7919 AD - Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045. FAU - Li, Howard Y AU - Li HY AD - Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045. AD - Department of Veterans Affairs Medical Center, Denver, CO 80220. FAU - Kwak, Jeff W AU - Kwak JW AUID- ORCID: 0000-0003-1481-3654 AD - Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045. FAU - Hopp, Katharina AU - Hopp K AD - Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045. FAU - Weiser-Evans, Mary C M AU - Weiser-Evans MCM AD - Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045. FAU - Heasley, Lynn E AU - Heasley LE AD - Department of Veterans Affairs Medical Center, Denver, CO 80220. AD - Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045; and. FAU - Schenk, Erin L AU - Schenk EL AUID- ORCID: 0000-0001-9418-9948 AD - Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045. FAU - Clambey, Eric T AU - Clambey ET AUID- ORCID: 0000-0002-7972-9544 AD - Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045. FAU - Nemenoff, Raphael A AU - Nemenoff RA AUID- ORCID: 0000-0002-2369-2535 AD - Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045; raphael.nemenoff@cuanschutz.edu. LA - eng GR - P50 CA058187/CA/NCI NIH HHS/United States GR - P01 DK019928/DK/NIDDK NIH HHS/United States GR - R01 CA162226/CA/NCI NIH HHS/United States GR - P30 CA046934/CA/NCI NIH HHS/United States GR - T32 CA174648/CA/NCI NIH HHS/United States GR - R01 CA236222/CA/NCI NIH HHS/United States GR - UL1 TR001082/TR/NCATS NIH HHS/United States GR - K12 CA086913/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20200316 PL - United States TA - J Immunol JT - Journal of immunology (Baltimore, Md. : 1950) JID - 2985117R RN - 0 (Histocompatibility Antigens Class II) RN - 0 (MHC class II transactivator protein) RN - 0 (Nuclear Proteins) RN - 0 (Pdcd1 protein, mouse) RN - 0 (Programmed Cell Death 1 Receptor) RN - 0 (Trans-Activators) SB - IM MH - Adenocarcinoma of Lung/immunology/*therapy MH - Animals MH - Disease Models, Animal MH - Histocompatibility Antigens Class II/*genetics/immunology MH - Lung Neoplasms/immunology/*therapy MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Nuclear Proteins/*genetics/immunology MH - Programmed Cell Death 1 Receptor/immunology MH - Trans-Activators/*genetics/immunology MH - Tumor Microenvironment/*genetics/immunology PMC - PMC7472648 MID - NIHMS1622498 COIS- Disclosures The authors have no financial conflicts of interest. EDAT- 2020/03/18 06:00 MHDA- 2020/12/31 06:00 PMCR- 2020/09/04 CRDT- 2020/03/18 06:00 PHST- 2019/07/09 00:00 [received] PHST- 2020/02/07 00:00 [accepted] PHST- 2020/03/18 06:00 [pubmed] PHST- 2020/12/31 06:00 [medline] PHST- 2020/03/18 06:00 [entrez] PHST- 2020/09/04 00:00 [pmc-release] AID - jimmunol.1900778 [pii] AID - 10.4049/jimmunol.1900778 [doi] PST - ppublish SO - J Immunol. 2020 Apr 15;204(8):2295-2307. doi: 10.4049/jimmunol.1900778. Epub 2020 Mar 16.