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

卵巢癌相关的高死亡率是由于肿瘤导向治疗失败所致。 产生持久的治疗反应。最近，患有其他实体肿瘤的患者的持久存活率 使用免疫检查点抗体，然而在女性中没有观察到类似的结果 患有卵巢癌。我们实验室发表的研究表明，结合多(腺苷) 具有免疫检查点阻断的二磷酸核糖聚合酶(PARP)抑制剂可实现长时间的 卵巢癌模型的长期存活率。一项正在进行的临床试验的早期结果现在证明 该方案对女性复发性卵巢癌有显著的临床疗效。在此，我们建议 剖析导致观察到的这种组合的治疗协同作用的机制 免疫治疗与细胞毒疗法的最佳结合对女性慢性粒细胞白血病患者的长期益处 卵巢癌。这项研究的科学前提是积累动态的证据 肿瘤细胞与调节治疗反应的肿瘤微环境(TME)的相互作用 以及疾病的结果。我们的工作还表明，TME与肿瘤直接相互作用- 靶向药物以提高肿瘤清除能力。PARP抑制和CTLA4联合阻断导致 TME中产生干扰素γ的T细胞比例显著增加，这一效应持续了很长时间 在完成治疗后。我们发现干扰素γ增强了对PARP-1的肿瘤细胞毒作用。 在体外通过细胞内在机制抑制，干扰素γ是生存益处所必需的 活体观察。有证据表明，肿瘤环境中的条件显著调节了治疗 PARP抑制剂的有效性，被称为“背景合成致死性”，提供了一个最大限度地 TME的患者预后和靶向治疗效果。在这里，我们建议剖析细胞固有的 和-外在机制负责观察到的PARP抑制剂和 阻断CTLA4并开发与这些机制相关的治疗预测生物标记物用于临床 翻译。迅速采用免疫检查点抗体和PARP抑制剂进行治疗 对于卵巢癌和其他类型的肿瘤，这项建议可能通过以下方式立即产生临床影响 目前和计划中的临床试验。

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.