Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Oncology, Tangdu Hospital, Xi'an, Shaanxi, 710038, China.
Hum Pathol. 2021 Jul;113:20-27. doi: 10.1016/j.humpath.2021.04.003. Epub 2021 Apr 19.
High-grade serous ovarian carcinoma (HGSC) is the most lethal gynecologic malignancy. While immune checkpoint inhibitors against PD-L1 and CTLA-4 have shown significant effects in multiple tumor types, the response rate to single-agent immune checkpoint inhibitors is low in HGSC. Alternative biomarkers and targets must be identified to guide patient selection and new therapeutic strategies in HGSC. Here, we aim to investigate the clinical significance of novel immune modulators, including B7-H4, IDO1, Tim3, IL6, and IL-8, in patients with HGSC. A total of 48 patients with HGSCs, comprising 24 cases that were sensitive and 24 that were resistant to standard paclitaxel and carboplatin chemotherapy, were selected for our initial analysis. A NanoString assay including 33 immune-related genes was used to compare the expression of different immune regulatory molecules in the sensitive and resistant groups. Differentially expressed proteins were verified using multiplex immunohistochemical staining on tissue arrays of 202 patients with HGSCs who underwent primary surgery at MDACC. We analyzed the expression levels of immune checkpoints and compared expression profiles with clinicopathologic features including response, progression-free survival, and overall survival. HGSC tumors resistant to therapy expressed higher levels of B7-H4 (69.3%), IDO1 (71.8%), Tim3 (89.1%), and inflammatory factors IL-6 and IL-8, and expressed higher Tim3 in stromal components. High expression of B7-H4 and IDO1 was associated with significantly lower overall survival and progression-free survival. B7-H4 and IDO1 were co-expressed in 49.1% of studied cases. A panel of immunomodulatory proteins including B7-H4, IDO1, Tim3, IL-6, and IL-8 are expressed at high levels in HGSCs. These modulators represent novel targets to enhance immunotherapy in patients with HGSCs.
高级别浆液性卵巢癌（HGSC）是最致命的妇科恶性肿瘤。尽管针对 PD-L1 和 CTLA-4 的免疫检查点抑制剂在多种肿瘤类型中显示出显著疗效，但单药免疫检查点抑制剂在 HGSC 中的反应率较低。必须确定替代生物标志物和靶标，以指导 HGSC 患者的选择和新的治疗策略。在这里，我们旨在研究新型免疫调节剂，包括 B7-H4、IDO1、Tim3、IL6 和 IL-8，在 HGSC 患者中的临床意义。我们选择了 48 名 HGSC 患者进行初步分析，其中 24 名对标准紫杉醇和卡铂化疗敏感，24 名耐药。使用包含 33 个免疫相关基因的 NanoString 检测比较了敏感组和耐药组中不同免疫调节分子的表达。在 MDACC 接受初次手术的 202 名 HGSC 患者的组织阵列上使用多重免疫组化染色验证了差异表达蛋白。我们分析了免疫检查点的表达水平，并将表达谱与包括反应、无进展生存期和总生存期在内的临床病理特征进行了比较。对治疗耐药的 HGSC 肿瘤表达更高水平的 B7-H4（69.3%）、IDO1（71.8%）、Tim3（89.1%）和炎症因子 IL-6 和 IL-8，并在基质成分中表达更高的 Tim3。B7-H4 和 IDO1 的高表达与总生存期和无进展生存期显著降低相关。在研究的病例中，B7-H4 和 IDO1 共同表达占 49.1%。包括 B7-H4、IDO1、Tim3、IL-6 和 IL-8 在内的一组免疫调节蛋白在 HGSC 中高表达。这些调节剂代表了增强 HGSC 患者免疫治疗的新靶标。
