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Epigenetic and Transcriptional Control of the Epidermal Growth Factor Receptor Regulates the Tumor Immune Microenvironment in Pancreatic Cancer.

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.This article is highlighted in the In This Issue feature, p. 521.

SUBMITTER: Li J

PROVIDER: S-EPMC7933070 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Epigenetic and Transcriptional Control of the Epidermal Growth Factor Receptor Regulates the Tumor Immune Microenvironment in Pancreatic Cancer.

Li Jinyang J Yuan Salina S Norgard Robert J RJ Yan Fangxue F Sun Yu H YH Kim Il-Kyu IK Merrell Allyson J AJ Sela Yogev Y Jiang Yanqing Y Bhanu Natarajan V NV Garcia Benjamin A BA Vonderheide Robert H RH Blanco Andrés A Stanger Ben Z BZ

Cancer discovery 20201106 3

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 <i>in vivo</i> 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 memb ...[more]

PMID: 33158848

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Project description:ObjectiveTo review and summarize the characteristics of the tumor immune microenvironment (TIME) in EGFR-mutated non-small cell lung cancer (NSCLC) after EGFR-TKI treatment and its role in TKI resistance.BackgroundLung cancer is one of the most commonly diagnosed cancer and the leading cause of death from cancer in both men and women around the world. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are considered a first-line treatment for EGFR-mutated NSCLC. However, almost all patients eventually develop acquired resistance to EGFR-TKIs, with a median progression-free survival (PFS) of 9-14 months. As immunotherapy has developed, it has become apparent that interactions between the TIME and tumor cells also affect EGFR-TKI treatment. The TIME comprises a variety of components but previous studies of the TIME following EGFR-TKI therapy of NSCLC are inconsistent. Here, we reviewed the characteristics of the TIME in NSCLC after EGFR-TKI treatment and its role in TKI resistance.MethodsPubMed, Embase, and Web of Science were searched to July 1, 2021 with the following key words: "NSCLC", "EGFR", and "immunotherapy".ConclusionsThe TIME of EGFR-mutated NSCLC is different from that of non-mutated NSCLC, an explanation for EGFR-mutated NSCLC displaying a poor response to ICIs. The TIME of EGFR-mutated NSCLC also changes during treatment with EGFR-TKIs. The TIME in EGFR-TKI-resistant lung cancer can be summarized as follows: (I) compared with EGFR-TKI-sensitive tumors, EGFR-TKI-resistant tumors have a greater number of immunosuppressive cells and fewer immune-activated cells, while the tumor microenvironment is in an immunosuppressive state; (II) tumor cells and immunosuppressive cells secrete multiple negative immune regulatory factors, inhibit the recognition and presentation of tumor antigens and the antitumor effect of immune cells, resulting in immune escape; 3.EGFR-TKI-resistant tumors promote EMT. These three characteristics interact, resulting in a regulatory signaling network, which together leads to EGFR-TKI resistance.

Dataset Information

Epigenetic and Transcriptional Control of the Epidermal Growth Factor Receptor Regulates the Tumor Immune Microenvironment in Pancreatic Cancer.

Publications

Epigenetic and Transcriptional Control of the Epidermal Growth Factor Receptor Regulates the Tumor Immune Microenvironment in Pancreatic Cancer.

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