Mechanisms of selective therapeutic synergy of PARP-inhibition and CTLA4 blockade engaged by interferon-gamma in the ovarian tumor microenvironment

与卵巢癌相关的高死亡率是由于肿瘤导向治疗的失败， 产生持久的治疗反应。最近，其他实体瘤患者的持久生存率 使用免疫检查点抗体实现，但在女性中未观察到类似结果 卵巢癌我们实验室发表的工作表明，结合聚腺苷酸 二磷酸核糖）聚合酶（PARP）抑制剂与免疫检查点阻断可以实现长期的， 卵巢癌模型中的长期存活率。一项正在进行的临床试验的早期结果已经证明， 该方案在复发性卵巢癌患者中具有显著的临床疗效。在此，我们建议 剖析负责观察到的该组合的治疗协同作用的机制， 免疫治疗与细胞毒治疗方案的最佳整合对女性的长期益处 卵巢癌这项研究的科学前提是基于不断积累的证据， 肿瘤细胞与调节治疗反应的肿瘤微环境（TME）之间的相互作用 和疾病结果。我们的工作还表明，TME直接与肿瘤相互作用- 靶向药物以增强肿瘤清除。PARP抑制和CTLA 4阻断的组合导致 在TME中产生IFNγ的T细胞比例显著增加，这种作用持续很长时间 治疗结束后。我们发现IFNγ增强了对PARP的肿瘤细胞毒性， 在体外通过细胞内在机制抑制，且IFNγ是存活益处所需 在体内观察。有证据表明，肿瘤环境中的条件显着调节治疗 PARP抑制剂的功效，被称为“背景合成致死性”，提供了一个机会， 患者结局和TME的目标治疗效果。在这里，我们建议解剖细胞的内在 和-负责观察到的PARP抑制剂的治疗协同作用的外在机制， CTLA 4阻断并开发与这些机制相关的治疗预测生物标志物，用于临床 翻译.随着免疫检查点抗体和PARP抑制剂的迅速采用， 卵巢癌和其他肿瘤类型，这项建议有可能立即临床影响， 当前和计划的临床试验。

The high mortality rate associated with ovarian cancer results from the failure of tumor-directed therapy to produce lasting treatment responses. Durable survival in patients with other solid tumors has recently been achieved using immune checkpoint antibodies, however similar results have not been observed in women with ovarian cancer. Published work from our lab demonstrates that combining poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors with immune checkpoint blockade can achieve long- term survival in ovarian cancer models. Early results from an ongoing clinical trial have now demonstrated significant clinical efficacy of this regimen in women with recurrent ovarian cancer. Here we propose to dissect the mechanisms responsible for the observed therapeutic synergy of this combination to enable the optimal integration of immune therapy with cytotoxic regimens for long-term benefit in women with ovarian cancer. The scientific premise for this study is based accumulating evidence of a dynamic interaction between tumor cells and the tumor microenvironment (TME) that regulates treatment response and disease outcomes. Our work additionally demonstrates that the TME interacts directly with tumor- targeted agents to enhance tumor clearance. Combined PARP-inhibition and CTLA4 blockade resulted in a significant increase in the proportion of T cells producing IFNγ in the TME, an effect which persisted long after completion of therapy. We found that IFNγ enhanced tumor cytotoxicity in response to PARP- inhibition through a cell-intrinsic mechanism in vitro, and that IFNγ was required for the survival benefit observed in vivo. Evidence that conditions in the tumor environment significantly modulate the therapeutic efficacy of PARP-inhibitors, termed “contextual synthetic lethality”, presents an opportunity to maximize patient outcomes and target treatment effects to the TME. Here we propose to dissect the cell-intrinsic and –extrinsic mechanisms responsible for the observed therapeutic synergy of PARP inhibitors and CTLA4 blockade and to develop a treatment predictive biomarker linked to these mechanisms for clinical translation. With the rapid adoption of immune checkpoint antibodies and PARP-inhibitors for the treatment of ovarian cancer and other tumor types, this proposal has potential for immediate clinical impact through current and planned clinical trials.