C5aR1 blockade reshapes immunosuppressive tumor microenvironment and synergizes with immune checkpoint blockade therapy in high-grade serous ovarian cancer.

IF 7.2 2区 医学
Oncoimmunology Pub Date : 2023-09-30 eCollection Date: 2023-01-01 DOI:10.1080/2162402X.2023.2261242
Chen Zhang, Kankan Cao, Moran Yang, Yiying Wang, Mengdi He, Jiaqi Lu, Yan Huang, Guodong Zhang, Haiou Liu
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引用次数: 0

Abstract

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.

C5aR1阻断重塑免疫抑制肿瘤微环境,并与免疫检查点阻断疗法协同治疗高级别浆液性卵巢癌症。
高粒径浆液性癌症(HGSC)对靶向PD-1/PD-L1单药治疗的免疫检查点阻断(ICB)反应适度,被M2极化肿瘤相关巨噬细胞(TAMs)和调节性T(Treg)细胞密集浸润。补体C5a/C5aR1轴有助于实体瘤中TAMs的免疫抑制表型的编程,并代表了治疗HGSC的一个有前途的免疫调节靶点。在此,我们旨在确定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队列中C5aR1的表达及其与肿瘤浸润免疫细胞的关系(n = 120)和新鲜HGSC组织(n = 36)。异种移植物的转录组学分析描绘了驱动PMX53免疫调节活性的机制,PMX53是一种口服生物可利用的C5aR1抑制剂。在离体肿瘤培养物和癌症基因组图谱(TCGA)数据集中证实了治疗相关性。C5aR1的表达独立地预测了惨淡的预后,并与HGSC的免疫逃避亚型有关,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)的浸润增加和CD8+T功能受损。PMX53在几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分析显示,C5aR1在TAMs中主要表达,在C5aR1+TAMs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有关。因此,C5aR1的丰度可以预测HGSC的不良预后,结合PD-L1可以作为一种新的预测性生物标志物来指导治疗选择。
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来源期刊
Oncoimmunology
Oncoimmunology ONCOLOGY-IMMUNOLOGY
CiteScore
12.80
自引率
2.80%
发文量
276
期刊介绍: Tumor immunology explores the natural and therapy-induced recognition of cancers, along with the complex interplay between oncogenesis, inflammation, and immunosurveillance. In response to recent advancements, a new journal, OncoImmunology, is being launched to specifically address tumor immunology. The field has seen significant progress with the clinical demonstration and FDA approval of anticancer immunotherapies. There's also growing evidence suggesting that many current chemotherapeutic agents rely on immune effectors for their efficacy. While oncologists have historically utilized chemotherapeutic and radiotherapeutic regimens successfully, they may have unwittingly leveraged the immune system's ability to recognize tumor-specific antigens and control cancer growth. Consequently, immunological biomarkers are increasingly crucial for cancer prognosis and predicting chemotherapy efficacy. There's strong support for combining conventional anticancer therapies with immunotherapies. OncoImmunology will welcome high-profile submissions spanning fundamental, translational, and clinical aspects of tumor immunology, including solid and hematological cancers, inflammation, and both innate and acquired immune responses.
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