LncRNA EPIC1 induces immunotherapy resistance by activating EZH2 in breast cancer

摘要：2021年7月26日，FDA批准了抗PD1免疫疗法pembrolizumab(Keytruda®， 默克公司(Merck)，用于三阴性乳腺癌(TNBC)患者。尽管在以下方面取得了重大进展 乳腺癌免疫治疗，对免疫治疗的抵抗仍然是持久生存的主要障碍 有益于乳腺癌患者。迫切需要有针对性的机制来克服治疗耐药性 需要的。新的证据表明，长非编码RNA基因(LncRNAs)在 肿瘤免疫。在我们最近的出版物中，我们已经确定了一种特定表达的lncRNA，EPIC1 通过激活EZH2蛋白抑制抗肿瘤免疫反应。基于我们的 初步数据，我们假设：(A)EPIC1通过激活EZH2诱导免疫治疗抵抗 乳腺癌；和(B)EZH2抑制剂他西莫司汀(TAZVERIK®)可增强对抗PD1的反应 EPIC1过表达乳腺癌的治疗。我们设计了三个目标来检验我们的假设。目标1 将确定EPIC1-EZH2轴与人类乳腺肿瘤免疫抑制的关系 癌症样本。目的2将剖析EPIC1-EZH2轴调节肿瘤免疫的机制。 目的3将测试他赛托斯特单独或与抗PD1抗体联合治疗人源化乳腺癌的疗效。 老鼠模型。我们已经组建了一支包括基础、翻译和临床调查人员的团队，他们已经 在乳腺癌病理学、RNA生物学和免疫治疗方面有丰富的经验进行建议 研究。我们的项目将提供关键的临床前数据和生物标记物，用于FDA- 批准用于乳腺癌患者的抗癌药物。

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.