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Abstract：
High-grade serous ovarian carcinoma (HGSC) is the most lethal gynecologic malignancy characterized by resistance to chemotherapy and high rates of recurrence. HGSC tumors display a high prevalence of tumor suppressor gene loss. Given the type 1 interferon regulatory function of BRCA1 and PTENgenes and their associated contrasting T-cell infiltrated and non-infiltrated tumor immune microenvironment (TIME) states, respectively, in this study we investigated the potential of stimulator of interferon genes (STING) pathway activation in improving overall survival via enhancing chemotherapy response, specifically in tumors with PTEN deficiency.
Expression of PTEN protein was evaluated in tissue microarrays generated using pretreatment tumors collected from a cohort of 110 patients with HGSC. Multiplex immunofluorescence staining was performed to determine spatial profiles and density of selected lymphoid and myeloid cells. In vivo studies using the syngeneic murine HGSC cell lines, ID8-Trp53 -/-; Pten -/- and ID8-Trp53 -/-; Brca1 -/-, were conducted to characterize the TIME and response to carboplatin chemotherapy in combination with exogenous STING activation therapy.
Patient tumors with absence of PTEN protein exhibited a significantly decreased disease specific survival and intraepithelial CD68+ macrophage infiltration as compared with intact PTEN expression. In vivo studies demonstrated that Pten-deficient ovarian cancer cells establish an immunosuppressed TIME characterized by increased proportions of M2-like macrophages, GR1+MDSCs in the ascites, and reduced effector CD8+ cytotoxic T-cell function compared with Brca1-deficient cells; further, tumors from mice injected with Pten-deficient ID8 cells exhibited an aggressive behavior due to suppressive macrophage dominance in the malignant ascites. In combination with chemotherapy, exogenous STING activation resulted in longer overall survival in mice injected with Pten-deficient ID8 cells, reprogrammed intraperitoneal M2-like macrophages derived from Pten-deficient ascites to M1-like phenotype and rescued CD8+ cytotoxic T-cell activation.
This study reveals the importance of considering the influence of cancer cell intrinsic genetic alterations on the TIME for therapeutic selection. We establish the rationale for the optimal incorporation of interferon activating therapies as a novel combination strategy in PTEN-deficient HGSC.
Expression of PTEN protein was evaluated in tissue microarrays generated using pretreatment tumors collected from a cohort of 110 patients with HGSC. Multiplex immunofluorescence staining was performed to determine spatial profiles and density of selected lymphoid and myeloid cells. In vivo studies using the syngeneic murine HGSC cell lines, ID8-Trp53 -/-; Pten -/- and ID8-Trp53 -/-; Brca1 -/-, were conducted to characterize the TIME and response to carboplatin chemotherapy in combination with exogenous STING activation therapy.
Patient tumors with absence of PTEN protein exhibited a significantly decreased disease specific survival and intraepithelial CD68+ macrophage infiltration as compared with intact PTEN expression. In vivo studies demonstrated that Pten-deficient ovarian cancer cells establish an immunosuppressed TIME characterized by increased proportions of M2-like macrophages, GR1+MDSCs in the ascites, and reduced effector CD8+ cytotoxic T-cell function compared with Brca1-deficient cells; further, tumors from mice injected with Pten-deficient ID8 cells exhibited an aggressive behavior due to suppressive macrophage dominance in the malignant ascites. In combination with chemotherapy, exogenous STING activation resulted in longer overall survival in mice injected with Pten-deficient ID8 cells, reprogrammed intraperitoneal M2-like macrophages derived from Pten-deficient ascites to M1-like phenotype and rescued CD8+ cytotoxic T-cell activation.
This study reveals the importance of considering the influence of cancer cell intrinsic genetic alterations on the TIME for therapeutic selection. We establish the rationale for the optimal incorporation of interferon activating therapies as a novel combination strategy in PTEN-deficient HGSC.
摘要：
背景：高级别浆液性卵巢癌（HGSC）是最致命的妇科恶性肿瘤，其特征是对化疗耐药和高复发率。HGSC肿瘤表现出抑癌基因丢失的高患病率。鉴于BRCA1和PTEN基因的1型干扰素调节功能及其相关的对比T细胞浸润和非浸润肿瘤免疫微环境（TIME）状态，分别,在这项研究中，我们研究了干扰素基因刺激因子（STING）途径激活在通过增强化疗反应改善总体生存率方面的潜力，特别是在PTEN缺乏的肿瘤中。
方法:在组织微阵列中评估PTEN蛋白的表达,所述组织微阵列使用从110名患有HGSC的患者的队列收集的预处理肿瘤产生。进行多重免疫荧光染色以确定所选淋巴和骨髓细胞的空间分布和密度。使用同系小鼠HGSC细胞系的体内研究，ID8-Trp53-/-;Pten-/-和ID8-Trp53-/-;Brca1-/-,进行了表征时间和对卡铂化疗联合外源性STING激活疗法的反应。
结果：与完整的PTEN表达相比，缺乏PTEN蛋白的患者肿瘤表现出疾病特异性存活和上皮内CD68+巨噬细胞浸润的显著降低。体内研究表明，Pten缺乏的卵巢癌细胞建立了免疫抑制的时间，其特征是M2样巨噬细胞的比例增加，腹水中的GR1+MDSCs，与Brca1缺陷细胞相比，效应CD8+细胞毒性T细胞功能降低;进一步，注射Pten缺陷型ID8细胞的小鼠肿瘤由于抑制恶性腹水中的巨噬细胞优势而表现出攻击行为。联合化疗，外源性STING激活导致注射Pten缺陷ID8细胞的小鼠的总生存期更长，将Pten缺陷性腹水衍生的腹膜内M2样巨噬细胞重编程为M1样表型，并挽救了CD8细胞毒性T细胞活化。
结论：本研究揭示了考虑癌细胞内在遗传改变对治疗选择时间的影响的重要性。我们建立了最佳掺入干扰素激活疗法作为PTEN缺陷型HGSC的新型组合策略的基本原理。
方法:在组织微阵列中评估PTEN蛋白的表达,所述组织微阵列使用从110名患有HGSC的患者的队列收集的预处理肿瘤产生。进行多重免疫荧光染色以确定所选淋巴和骨髓细胞的空间分布和密度。使用同系小鼠HGSC细胞系的体内研究，ID8-Trp53-/-;Pten-/-和ID8-Trp53-/-;Brca1-/-,进行了表征时间和对卡铂化疗联合外源性STING激活疗法的反应。
结果：与完整的PTEN表达相比，缺乏PTEN蛋白的患者肿瘤表现出疾病特异性存活和上皮内CD68+巨噬细胞浸润的显著降低。体内研究表明，Pten缺乏的卵巢癌细胞建立了免疫抑制的时间，其特征是M2样巨噬细胞的比例增加，腹水中的GR1+MDSCs，与Brca1缺陷细胞相比，效应CD8+细胞毒性T细胞功能降低;进一步，注射Pten缺陷型ID8细胞的小鼠肿瘤由于抑制恶性腹水中的巨噬细胞优势而表现出攻击行为。联合化疗，外源性STING激活导致注射Pten缺陷ID8细胞的小鼠的总生存期更长，将Pten缺陷性腹水衍生的腹膜内M2样巨噬细胞重编程为M1样表型，并挽救了CD8细胞毒性T细胞活化。
结论：本研究揭示了考虑癌细胞内在遗传改变对治疗选择时间的影响的重要性。我们建立了最佳掺入干扰素激活疗法作为PTEN缺陷型HGSC的新型组合策略的基本原理。
