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. 2023 Sep 30;12(1):2261242.
doi: 10.1080/2162402X.2023.2261242. eCollection 2023.

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

Chen Zhang  1 , Kankan Cao  1 , Moran Yang  1 , Yiying Wang  1 , Mengdi He  1 , Jiaqi Lu  2 , Yan Huang  3 , Guodong Zhang  1   2 , Haiou Liu  1
Affiliations

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

Chen Zhang et al. Oncoimmunology. .

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.

Keywords: High-grade serous ovarian cancer; immunotherapy; prognosis; tumor microenvironment; tumor-associated macrophages.

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Conflict of interest statement

No potential conflict of interest was reported by the author(s).

Figures

Figure 1.
Figure 1.
C5aR1 expression associates with unfavorable outcome in HGSC.
Figure 2.
Figure 2.
C5aR1 expression correlates with immunosuppressive tumor microenvironment in HGSC.
Figure 3.
Figure 3.
Inhibition of C5aR1 retards tumor growth and reactivate anti-tumor immunity.
Figure 4.
Figure 4.
Inhibition of C5aR1 enhances the anti-tumor efficacy of anti-PD-1 immunotherapy.
Figure 5.
Figure 5.
C5aR1 is mainly expressed on macrophages and contributes to immunosuppressive phenotype.
Figure 6.
Figure 6.
C5aR1 and PD-L1 expression panel correlates with oncogenic pathway activity, therapeutic signatures and molecular alterations.
See this image and copyright information in PMC

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