Abstract
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 in- hibition of the methyltransferase enhancer of zeste homolog 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 his- tone 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 re- sults 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 sup- port clinical translation of this combination therapy for treatment of this deadly tumor type.
Document Type
Article
Publication Date
2024
Digital Object Identifier (DOI)
https://doi.org/10.1158/2767-9764.CRC-23-0399
Funding Information
The authors thank Dr. David Powell for extensive help with the MRI scan- ning, and Drs. Doug Harrison and Jim Begley at the University of Kentucky A&S Imaging Center for preparation of the scRNA-seq samples and initial analysis. We thank Dr. Teresa Fan’s laboratory for providing the PDX samples to make the PDTs. This work was supported in part by NCI K22 CA201036, NCI R01 CA237643, NIGMS P20 GM121327-03, V Foundation Scholar Award V2017-010, American Cancer Society Grants IRG-85-001-25 and 133123-RSG- 19-081-01-TBG, the American Institute for Cancer Research Grant 710410 2018, the AACR-Bayer Innovation and Discovery Grant, Grant Number 18- 80-44-BRAI, the American Lung Association Innovation Award IA-046815, and the Markey Research Women Strong Distinguished Researcher Award 3048116064 (C.F. Brainson), NCI T32 CA165990 (D.R. Plaugher), Markey STRONG Scholars Program through the American Cancer Society IRG-19- 140-31 (E.M. Skaggs), and NIEHS T32 5T32ES007266 (T.J. DuCote). This research was also supported by the Biostatistics & Bioinformatics, Cancer Re- search Informatics, Oncogenomics, Biospecimen Procurement & Translational Pathology, Flow Cytometry & Immune Monitoring Shared Resource Facilities, and pilot grant funding from the University of Kentucky Markey Cancer Center (P30 CA177558).
Repository Citation
DuCote, Tanner; Song, Xiulong; Naughton, Kassandra J.; Chen, Fan; Plaugher, Daniel; Childress, Avery R.; Gellert, Abigail R.; Skaggs, Erika M.; Qu, Xufeng; Liu, Jinze; Liu, Jinpeng; Li, Fei; Wong, Kwok-Kin; and Brainson, Christine F., "EZH2 Inhibition Promotes Tumor Immunogenicity in Lung Squamous Cell Carcinomas" (2024). Markey Cancer Center Faculty Publications. 270.
https://uknowledge.uky.edu/markey_facpub/270
Notes/Citation Information
This open access article is distributed under the Creative Commons Attribution 4.0 International (CC BY 4.0) license. © 2024 The Authors; Published by the American Association for Cancer Research