Epigenetic and transcriptional control of the epidermal growth factor receptor regulates the tumor immune microenvironment in pancreatic cancer

Jinyang Li, Salina Yuan, Robert J. Norgard, Fangxue Yan, Yu H. Sun, Il Kyu Kim, Allyson J. Merrell, Yogev Sela, Yanqing Jiang, Natarajan V. Bhanu, Benjamin A. Garcia, Robert H. Vonderheide, Andrés Blanco, Ben Z. Stanger

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Although immunotherapy has revolutionized cancer care, patients with pancreatic ductal adenocarcinoma (PDA) rarely respond to these treatments, a failure that is attributed to poor infiltration and activation of T cells in the tumor microenvironment (TME). We performed an in vivo CRISPR screen and identified lysine demethylase 3A (KDM3A) as a potent epigenetic regulator of immunotherapy response in PDA. Mechanistically, KDM3A acts through Krueppel-like factor 5 (KLF5) and SMAD family member 4 (SMAD4) to regulate the expression of the epidermal growth factor receptor (EGFR). Ablation of KDM3A, KLF5, SMAD4, or EGFR in tumor cells altered the immune TME and sensitized tumors to combination immunotherapy, whereas treatment of established tumors with an EGFR inhibitor, erlotinib, prompted a dose-dependent increase in intratumoral T cells. This study defines an epigenetic–transcriptional mechanism by which tumor cells modulate their immune microenvironment and highlights the potential of EGFR inhibitors as immunotherapy sensitizers in PDA. SIGnIFICAnCE: PDA remains refractory to immunotherapies. Here, we performed an in vivo CRISPR screen and identified an epigenetic–transcriptional network that regulates antitumor immunity by converging on EGFR. Pharmacologic inhibition of EGFR is sufficient to rewire the immune microenvironment. These results offer a readily accessible immunotherapy-sensitizing strategy for PDA.

Original languageEnglish
Pages (from-to)736-753
Number of pages18
JournalCancer discovery
Volume11
Issue number3
DOIs
StatePublished - Mar 2021

Fingerprint

Dive into the research topics of 'Epigenetic and transcriptional control of the epidermal growth factor receptor regulates the tumor immune microenvironment in pancreatic cancer'. Together they form a unique fingerprint.

Cite this