2. Academic Validation
  3. EZH2 inhibition promotes tumor immunogenicity in lung squamous cell carcinomas

EZH2 inhibition promotes tumor immunogenicity in lung squamous cell carcinomas

  • bioRxiv. 2023 Jun 8:2023.06.06.543919. doi: 10.1101/2023.06.06.543919.
Tanner J DuCote 1,  Xiulong Song 1,  Kassandra J Naughton 1,  Fan Chen 1,  Daniel R Plaugher 1,  Avery R Childress 1,  Abigail R Edgin 1,  Xufeng Qu 2,  Jinze Liu 2 3,  Jinpeng Liu 4,  Fei Li 5,  Kwok-Kin Wong 5,  Christine F Brainson 1 6
Affiliations

Affiliations

  • 1 Department of Toxicology and Cancer Biology, University of Kentucky, Lexington KY 40536 USA.
  • 2 Department of Biostatistics, Virginia Commonwealth University, Richmond, VA 23219 USA.
  • 3 Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23219 USA.
  • 4 Department of Cancer Biostatistics, University of Kentucky, Lexington KY 40536 USA.
  • 5 Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York University, New York, NY 10016 USA.
  • 6 Markey Cancer Center, University of Kentucky, Lexington KY 40536 USA.
PMID: 37333199 DOI: 10.1101/2023.06.06.543919
Abstract

Two important factors that contribute to resistance to immune checkpoint inhibitors (ICIs) are an immune-suppressive microenvironment and limited antigen presentation by tumor cells. In this study, we examine if inhibition of the methyltransferase EZH2 can increase ICI response in lung squamous cell carcinomas (LSCCs). Our in vitro experiments using 2D human Cancer cell lines as well as 3D murine and patient derived organoids treated with two inhibitors of the EZH2 plus interferon-γ (IFNγ) showed that EZH2 inhibition leads to expression of both major histocompatibility complex class I and II (MHCI/II) expression at both the mRNA and protein levels. ChIP-sequencing confirmed loss of EZH2-mediated histone marks and gain of activating histone marks at key loci. Further, 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 towards more tumor suppressive phenotypes in EZH2 Inhibitor treated tumors. These results indicate that this therapeutic modality could increase ICI responses in patients undergoing treatment for LSCC.

Keywords

EZH2; MHC; epigenetics; immunotherapy; neutrophils.

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