دورية أكاديمية
أعرض في EDS

EZH2 Inhibition Promotes Tumor Immunogenicity in Lung Squamous Cell Carcinomas.

التفاصيل البيبلوغرافية
العنوان: EZH2 Inhibition Promotes Tumor Immunogenicity in Lung Squamous Cell Carcinomas.
المؤلفون: DuCote TJ; Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky., Song X; Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky., Naughton KJ; Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky., Chen F; Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky., Plaugher DR; Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky., Childress AR; Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky., Gellert AR; Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky., Skaggs EM; Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky., Qu X; Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia., Liu J; Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia.; Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia., Liu J; Department of Cancer Biostatistics, University of Kentucky, Lexington, Kentucky., Li F; Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York University, New York, New York., Wong KK; Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York University, New York, New York., Brainson CF; Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky.; Markey Cancer Center, University of Kentucky, Lexington, Kentucky.
المصدر: Cancer research communications [Cancer Res Commun] 2024 Feb 13; Vol. 4 (2), pp. 388-403.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural
اللغة: English
بيانات الدورية: Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 9918281580506676 Publication Model: Print Cited Medium: Internet ISSN: 2767-9764 (Electronic) Linking ISSN: 27679764 NLM ISO Abbreviation: Cancer Res Commun Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [Philadelphia, Pennsylvania] : American Association for Cancer Research, [2021]-
مواضيع طبية MeSH: Carcinoma, Non-Small-Cell Lung* , Carcinoma, Squamous Cell*/drug therapy , Lung Neoplasms*/drug therapy, Humans ; Mice ; Animals ; Cell Line ; Enzyme Inhibitors ; Lung/pathology ; Tumor Microenvironment ; Enhancer of Zeste Homolog 2 Protein/genetics
مستخلص: 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 IFNγ 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.
(© 2024 The Authors; Published by the American Association for Cancer Research.)
التعليقات: Update of: bioRxiv. 2023 Jun 08;:. (PMID: 37333199)
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معلومات مُعتمدة: P20 GM121327 United States GM NIGMS NIH HHS; T32 ES007266 United States ES NIEHS NIH HHS; P30 CA177558 United States CA NCI NIH HHS; K22 CA201036 United States CA NCI NIH HHS; R01 CA237643 United States CA NCI NIH HHS; T32 CA165990 United States CA NCI NIH HHS
المشرفين على المادة: 0 (Enzyme Inhibitors)
EC 2.1.1.43 (EZH2 protein, human)
EC 2.1.1.43 (Enhancer of Zeste Homolog 2 Protein)
تواريخ الأحداث: Date Created: 20240124 Date Completed: 20240214 Latest Revision: 20240313
رمز التحديث: 20240314
مُعرف محوري في PubMed: PMC10863487
DOI: 10.1158/2767-9764.CRC-23-0399
PMID: 38265267
قاعدة البيانات: MEDLINE
الوصف
تدمد:2767-9764
DOI:10.1158/2767-9764.CRC-23-0399