组蛋白去甲基化酶抑制剂GSK-J4对卵巢癌免疫微环境的激活及对PD-1阻断治疗的增效作用研究

Anti-PD-1 antibody has been widely used for clinical cancer therapy as it can activate T cells and potentiate antitumor immunity. Due to the poor response of ovarian cancer patients to anti-PD-1 antibody immunotherapy, ovarian cancer which bearing the highest mortality in gynecologic carcinomas, is not a part of indications of anti-PD-1 antibody. Therefore, there is imperative that finding a new target to enhance anti-PD-1 immunotherapy in ovarian cancer..Tumor Associated Macrophages (TAMs) are the most abundant and common immunosuppressive cells in tumor micro-environment. TAMs can promote tumoral immune escape by inhibiting the anti-tumor function of T cells. In our previous study, the increased JMJD3 expression was observed in M2-like macrophages induced by apoptotic cells and the M2-like phenotype can be blocked by GSK-J4. Therefore, in the present study, we plan to combine anti-PD-1 antibody with JMJD3 inhibitor-GSK-J4 in ovarian cancer. This new combination may enhance the anti-tumor effect of anti-PD-1 antibody by reversing M2-like phenotype of macrophage and provide a new option for ovarian immunotherapy.

PD-1抗体可通过激活T细胞，恢复人体抗肿瘤免疫，目前已应用于多种肿瘤的临床治疗。卵巢癌作为死亡率最高的妇科肿瘤，由于患者对PD-1抗体治疗的反应率不高，目前未纳入为任何PD-1抗体的治疗适应症。所以寻找一种可增强卵巢癌中PD-1抗体疗效的新靶点,对卵巢癌免疫治疗具有重要意义。.肿瘤相关巨噬细胞（TAMs）是肿瘤微环境中最常见的免疫抑制细胞，可通过抑制微环境中T细胞的功能，协助肿瘤免疫逃逸。本项目前期研究中已经发现，JMJD3在凋亡肿瘤细胞等因素诱导的M2样抑制性巨噬细胞中高表达，通过GSK-J4干预JMJD3分子去甲基化酶活性可有效抑制巨噬细胞M2样极化。因此本项目拟在卵巢癌免疫治疗中联合使用JMJD3去甲基化酶活性抑制剂GSK-J4，尝试通过逆转微环境中巨噬细胞M2表型，增强PD-1抗体对卵巢癌的疗效，为卵巢癌PD-1抗体阻断治疗提供新的联合用药思路。

作为免疫检查点抑制剂，抗PD-1抗体可激活T细胞增强抗肿瘤免疫，目前已应用于多种肿瘤的临床治疗。卵巢癌是死亡率最高的妇科肿瘤，但由于卵巢癌患者对PD-1抗体治疗的反应率低，目前尚未被纳入PD-1抗体治疗的适应症。所以寻找一种增强卵巢癌中抗PD-1抗体疗效的新方法，对卵巢癌患者的免疫治疗具有重要意义。.本项目中我们使用组蛋白去甲基化酶JMJD3的抑制剂GSK-J4，在小鼠ID8卵巢癌中实现了微环境中巨噬细胞M2样表型的逆转，增加了M1/M2比例，同时还激活了微环境中抗肿瘤的T细胞免疫。在此基础上我们联用GSK-J4和抗PD-1抗体，通过多重激活抗肿瘤免疫的方式，在小鼠卵巢癌模型中取得了良好疗效。为了明确其具体作用机制，我们通过抗体和试剂对小鼠体内巨噬细胞和CD8+T细胞进行了清除。研究发现，GSK-J4主要通过诱导巨噬细胞的表型的改变来缓解免疫抑制，增效抗PD-1抗体疗效。可见机体固有免疫细胞，特别是巨噬细胞，在抗肿瘤免疫中具有不可忽视的作用。这一结果提示我们，通过表观调节药物调节免疫细胞功能表型，缓解微环境免疫抑制是一种行之有效的抗肿瘤免疫治疗手段。这一发现将为PD-1抗体耐药的卵巢癌患者提供新的治疗思路。