Project 3: Hedgehog Inhibition to Enhance Response to ICI Therapy

摘要/摘要--项目3 当有效时，免疫检查点抑制物(ICI)治疗可以显著改善患者的预后 卵巢癌(OvCa)。然而，只有10%-20%的OvCa患者对ICI治疗有反应。低收入的一个原因 OvCa的ICI应答率可能与OvCa独特的免疫抑制肿瘤微环境(TME)有关，即 以免疫抑制的“M2”肿瘤相关巨噬细胞(TAM)浸润的致密间质为特征。我们 最近发现卵巢癌相关间充质干细胞(CA-MSC)协调和 免疫抑制OvCa TME；分化为表达成纤维细胞/肿瘤间质的BIGH3，募集 单核细胞向间质转化，促进表达M2 TAM的免疫抑制因子BIGH3的分化。 联合作用是CA-MSC驱动肿瘤免疫排斥和由此产生的对ICI的抵抗 心理治疗。重要的是，我们发现刺猬抑制剂(HHI)逆转了CA-MSC驱动的免疫排斥， 促进M2向M1的转换，恢复对脑梗塞治疗的应答。HHI疗法下调表达 BIGH3在CA-MSC和TAMS中的表达，并促进TAMS从M2表型向M1表型的转化。我们的 研究与许多最近的报告一致，HHI促进M1巨噬细胞极化并促进 抗肿瘤免疫。根据这些结果，我们假设CA-MSC产生了一个免疫抑制的Ovca TME和HHI将逆转CA-MSC介导免疫抑制并增强患者对ICI的反应 心理治疗。为了验证我们的假设，我们提出了以下具体目标：SA1。实施单臂阶段-II Atezolizumab(APD-L1)联合Vismodegib(HHI)治疗铂类药物的临床研究 耐药复发性卵巢癌。主要终点将是疗效和安全性。次要终端将是 响应持续时间、PFS、OS和翻译相关性。SA2：评估HHI对患者的影响 肿瘤免疫渗入和外周趋化因子，并确定变化是否预测治疗反应。 SA3：评价BIGH3作为肿瘤免疫排斥的驱动因素和免疫治疗靶点。vbl.使用 我们将评估BIGH3对免疫效应分子迁移和功能的影响，以及BIGH3对OvCa的影响 确定抗BIGH3治疗是否能增强小鼠肿瘤模型的ICI反应。 影响：这将是Ovca的第一个临床试验，以确定(I)HHI对患者ICI治疗的影响 (Ii)靶向CA-MSCs克服免疫抑制OvCa TME的作用。 相关的翻译研究将揭示潜在的预测治疗反应的生物标志物。最后，我们 将评估BIGH3作为一种免疫调节剂和新的治疗靶点。最终，我们相信这些研究 将影响OvCA患者对ICI治疗的反应，并将改善结果。

SUMMARY/ABSTRACT – PROJECT 3 When effective, immune checkpoint inhibitor (ICI) therapy can significantly improve the outcome of patients with ovarian cancer (OvCa). However, only 10-20% of OvCa patients respond to ICI therapy. One reason for the low ICI response rate of OvCa may be OvCa’s unique immunosuppressive tumor microenvironment (TME), which is typified by a dense stroma infiltrated by immunosuppressive ‘M2’ tumor associated macrophages (TAMs). We recently found that ovarian carcinoma-associated mesenchymal stem cells (CA-MSC) orchestrate an immunosuppressive OvCa TME; differentiating into BIGH3 expressing fibroblast/tumor stroma, recruiting monocytes to the stroma, and promoting the differentiation of immunosuppressive BIGH3 expressing ‘M2’ TAMs. The combined effect is that CA-MSC drive tumor immune exclusion and a resultant resistance to ICI therapy. Importantly, we find that hedgehog inhibitors (HHi) reverse CA-MSC-driven immune exclusion, promote M2 to M1 TAM conversion, and restore response to ICI therapy. HHi therapy down-regulates BIGH3 in CA-MSC and TAMs, and promotes the conversion of TAMs from an M2 to and M1 phenotype. Our studies are consistent with numerous recent reports that HHi promote M1 macrophage polarization and promote anti-tumor immunity. Based on these results, we hypothesize that CA-MSC create an immunosuppressive OvCa TME and that HHi will reverse CA-MSC mediated immune-suppression and enhance patient response to ICI therapy. To test our hypothesis, we propose the following specific aims: SA1. Conduct a single arm Phase-II clinical trial evaluating Atezolizumab (aPD-L1) combined with Vismodegib (HHi) in patients with platinum resistant recurrent ovarian cancer. Primary endpoints will be efficacy and safety. Secondary endpoints will be duration of response, PFS, OS and translational correlatives. SA2: Evaluate the impact of HHi on patients’ tumor immune infiltrates and peripheral chemokines and determine if changes predict response to therapy. SA3: To assess BIGH3 as a driver of tumor immune exclusion and immunotherapeutic target. Using murine models of OvCa, we will assess the impact of BIGH3 on immune effector migration and function and determine if anti-BIGH3 therapy can enhance ICI response in murine tumor models. IMPACT: This will be the first clinical trial in OvCa to determine (i) the impact of HHi on ICI therapy in patients with epithelial cancer, and (ii) the role of targeting CA-MSCs to overcome the immunosuppressive OvCa TME. Correlative translational studies will reveal potential predictive biomarkers of response to therapy. Finally, we will evaluate BIGH3 as an immune regulator and novel therapeutic target. Ultimately, we believe these studies will impact OvCa patient’s response to ICI therapy and will improve outcomes.