高级别浆液性卵巢癌 (HGSC) 对针对 PD-1/PD-L1 单一疗法的免疫检查点阻断 (ICB) 反应适中，并被 M2 极化肿瘤相关巨噬细胞 (TAM) 和调节性 T (Treg) 密集浸润。 ） 细胞。补体 C5a/C5aR1 轴有助于实体瘤中 TAM 免疫抑制表型的编程，并代表了治疗 HGSC 的有前途的免疫调节靶点。在这里，我们的目的是确定 C5aR1 在 HGSC 的预后、免疫微环境和免疫治疗反应中的相关性。通过免疫组织化学和流式细胞术评估训练组 (n = 120) 和新鲜 HGSC 组织 (n = 36) 中 C5aR1 的表达及其与肿瘤浸润免疫细胞的关系。异种移植物的转录组分析描绘了驱动 PMX53（一种口服生物可利用的 C5aR1 抑制剂）免疫调节活性的机制。治疗相关性在离体肿瘤培养物和癌症基因组图谱 (TCGA) 数据集中得到证实。 C5aR1 表达独立预测不良预后，并与 HGSC 的免疫逃避亚型相关，其特征是促肿瘤细胞（Treg 细胞、M2 极化巨噬细胞和中性粒细胞）浸润增加和 CD8 T 功能受损。 PMX53 在多种肿瘤类型中拮抗皮下肿瘤生长、调节免疫抑制机制并与 aPD-1 协同作用。单细胞 RNA-seq 分析揭示了 TAM 中 C5aR1 的主要表达，并且 C5aR1 TAM 中具有免疫抑制相关的表达特征。此外，C5aR1 和 PD-L1 的组合与特定的分子特征和匹配的临床反应注释相关。因此，C5aR1 的丰度可以预测 HGSC 的较差预后，而纳入 PD-L1 可以作为一种新型预测生物标志物来指导治疗选择。© 2023 作者。经泰勒许可出版

High-grade serous ovarian cancer (HGSC), with a modest response to immune checkpoint blockade (ICB) targeting PD-1/PD-L1 monotherapy, is densely infiltrated by M2-polarized tumor-associated macrophages (TAMs) and regulatory T (Treg) cells. The complement C5a/C5aR1 axis contributes to the programming of the immunosuppressive phenotype of TAMs in solid tumors and represents a promising immunomodulatory target for treating HGSCs. Here, we aimed to identify the relevance of C5aR1 in prognosis, immune microenvironment, and immunotherapy response in HGSCs. The expression and relationship of C5aR1 with tumor-infiltrating immune cells were assessed by immunohistochemistry and flow cytometry in the training cohort (n = 120) and fresh HGSC tissues (n = 36). Transcriptomic analyses of the xenografts delineated the mechanisms driving the immunomodulatory activity of PMX53, an orally bioavailable C5aR1 inhibitor. Therapeutic relevance was confirmed in ex vivo tumor cultures and The Cancer Genome Atlas (TCGA) datasets. C5aR1 expression independently predicted dismal prognosis and was linked to the immunoevasive subtype of HGSC, characterized by increased infiltration of pro-tumor cells (Treg cells, M2-polarized macrophages, and neutrophils) and impaired CD8+T functions. PMX53 antagonized subcutaneous tumor growth, modulated immunosuppressive mechanisms and synergized with aPD-1 in several tumor types. Single-cell RNA-seq analysis revealed predominant C5aR1 expression in TAMs, with an immunosuppressive-related expression signature in C5aR1+TAMs. Furthermore, the combination of C5aR1 and PD-L1 was associated with specific molecular characteristics and matched clinical response annotations. Therefore, the abundance of C5aR1 could predict an inferior prognosis in HGSCs, and incorporating PD-L1 may serve as a novel predictive biomarker to guide therapeutic options.© 2023 The Author(s). Published with license by Taylor & Francis Group, LLC.