LncRNA EPIC1 induces immunotherapy resistance by activating EZH2 in breast cancer

Summary:On July 26, 2021, the FDA approved the anti-PD1 immunotherapy pembrolizumab (Keytruda®, Merck) for triple negative breast cancer (TNBC) patients. Although significant progress has been made in breast cancer immunotherapy, resistance to immunotherapy remains a major obstacle to lasting survival benefit in breast cancer patients. Targetable mechanisms to overcome therapeutic resistance are urgently needed. Emerging evidence have shown that long noncoding RNA genes (lncRNAs) play essential roles in the tumor immunity. In our recent publication, we have identified a lncRNA, EPIC1, that is specifically expressed in tumor cells and suppresses the antitumor immune response through activating EZH2 protein. Based on our preliminary data, we hypothesize that (a) EPIC1 induces immunotherapy resistance by activating EZH2 in breast cancer; and (b) EZH2 inhibitor, tazemetostat (TAZVERIK®), may enhance responses to anti-PD1 therapy for EPIC1 overexpressed breast cancer. We have designed three aims to test our hypotheses. Aim 1 will determine the association of the EPIC1-EZH2 axis with tumor immune suppression in human breast cancer samples. Aim 2 will dissect the mechanism by which the EPIC1-EZH2 axis regulates tumor immunity. Aim 3 will test the efficacy of tazemetostat, alone or combined with anti-PD1, in humanized breast cancer mouse models. We have formed a team including basic, translational and clinical investigators, who have deep experience in breast cancer pathology, RNA biology, and immunotherapy to conduct the proposed research. Our project will provide key preclinical data and biomarkers for the combination of two FDA- approved cancer drugs for breast cancer patients.