PMID- 38265267 OWN - NLM STAT- MEDLINE DCOM- 20240214 LR - 20240313 IS - 2767-9764 (Electronic) IS - 2767-9764 (Linking) VI - 4 IP - 2 DP - 2024 Feb 13 TI - EZH2 Inhibition Promotes Tumor Immunogenicity in Lung Squamous Cell Carcinomas. PG - 388-403 LID - 10.1158/2767-9764.CRC-23-0399 [doi] AB - Two important factors that contribute to resistance to immune checkpoint inhibitors (ICI) are an immune-suppressive microenvironment and limited antigen presentation by tumor cells. In this study, we examine whether inhibition of the methyltransferase enhancer of zeste 2 (EZH2) can increase ICI response in lung squamous cell carcinomas (LSCC). Our in vitro experiments using two-dimensional human cancer cell lines as well as three-dimensional murine and patient-derived organoids treated with two inhibitors of the EZH2 plus IFNgamma showed that EZH2 inhibition leads to expression of both MHC class I and II (MHCI/II) expression at both the mRNA and protein levels. Chromatin immunoprecipitation sequencing confirmed loss of EZH2-mediated histone marks and gain of activating histone marks at key loci. Furthermore, we demonstrate strong tumor control in models of both autochthonous and syngeneic LSCC treated with anti-PD1 immunotherapy with EZH2 inhibition. Single-cell RNA sequencing and immune cell profiling demonstrated phenotypic changes toward more tumor suppressive phenotypes in EZH2 inhibitor-treated tumors. These results indicate that EZH2 inhibitors could increase ICI responses in patients undergoing treatment for LSCC. SIGNIFICANCE: The data described here show that inhibition of the epigenetic enzyme EZH2 allows derepression of multiple immunogenicity factors in LSCC, and that EZH2 inhibition alters myeloid cells in vivo. These data support clinical translation of this combination therapy for treatment of this deadly tumor type. CI - (c) 2024 The Authors; Published by the American Association for Cancer Research. FAU - DuCote, Tanner J AU - DuCote TJ AUID- ORCID: 0000-0002-4663-9542 AD - Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky. FAU - Song, Xiulong AU - Song X AUID- ORCID: 0009-0007-9117-0871 AD - Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky. FAU - Naughton, Kassandra J AU - Naughton KJ AUID- ORCID: 0009-0007-0400-0066 AD - Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky. FAU - Chen, Fan AU - Chen F AUID- ORCID: 0000-0002-1808-1668 AD - Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky. FAU - Plaugher, Daniel R AU - Plaugher DR AUID- ORCID: 0000-0002-4614-1058 AD - Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky. FAU - Childress, Avery R AU - Childress AR AUID- ORCID: 0009-0009-0933-6524 AD - Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky. FAU - Gellert, Abigail R AU - Gellert AR AUID- ORCID: 0000-0003-2702-5198 AD - Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky. FAU - Skaggs, Erika M AU - Skaggs EM AUID- ORCID: 0009-0007-6109-226X AD - Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky. FAU - Qu, Xufeng AU - Qu X AUID- ORCID: 0009-0007-1406-686X AD - Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia. FAU - Liu, Jinze AU - Liu J AUID- ORCID: 0000-0003-0555-9412 AD - Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia. AD - Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia. FAU - Liu, Jinpeng AU - Liu J AUID- ORCID: 0000-0003-4100-0237 AD - Department of Cancer Biostatistics, University of Kentucky, Lexington, Kentucky. FAU - Li, Fei AU - Li F AUID- ORCID: 0000-0002-1973-6611 AD - Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York University, New York, New York. FAU - Wong, Kwok-Kin AU - Wong KK AUID- ORCID: 0000-0001-6323-235X AD - Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York University, New York, New York. FAU - Brainson, Christine F AU - Brainson CF AUID- ORCID: 0000-0002-0854-5043 AD - Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky. AD - Markey Cancer Center, University of Kentucky, Lexington, Kentucky. LA - eng GR - P20 GM121327/GM/NIGMS NIH HHS/United States GR - T32 ES007266/ES/NIEHS NIH HHS/United States GR - P30 CA177558/CA/NCI NIH HHS/United States GR - K22 CA201036/CA/NCI NIH HHS/United States GR - R01 CA237643/CA/NCI NIH HHS/United States GR - T32 CA165990/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - Cancer Res Commun JT - Cancer research communications JID - 9918281580506676 RN - 0 (Enzyme Inhibitors) RN - EC 2.1.1.43 (EZH2 protein, human) RN - EC 2.1.1.43 (Enhancer of Zeste Homolog 2 Protein) SB - IM UOF - bioRxiv. 2023 Jun 08;:. PMID: 37333199 MH - Humans MH - Mice MH - Animals MH - *Carcinoma, Non-Small-Cell Lung MH - *Carcinoma, Squamous Cell/drug therapy MH - Cell Line MH - Enzyme Inhibitors MH - *Lung Neoplasms/drug therapy MH - Lung/pathology MH - Tumor Microenvironment MH - Enhancer of Zeste Homolog 2 Protein/genetics PMC - PMC10863487 EDAT- 2024/01/24 12:44 MHDA- 2024/02/13 12:44 PMCR- 2024/02/13 CRDT- 2024/01/24 09:33 PHST- 2023/09/17 00:00 [received] PHST- 2023/11/06 00:00 [revised] PHST- 2024/01/09 00:00 [accepted] PHST- 2024/02/13 12:44 [medline] PHST- 2024/01/24 12:44 [pubmed] PHST- 2024/01/24 09:33 [entrez] PHST- 2024/02/13 00:00 [pmc-release] AID - 734233 [pii] AID - CRC-23-0399 [pii] AID - 10.1158/2767-9764.CRC-23-0399 [doi] PST - ppublish SO - Cancer Res Commun. 2024 Feb 13;4(2):388-403. doi: 10.1158/2767-9764.CRC-23-0399.