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

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

Acknowledgments

This work was supported by the Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, the Obstetrics and Gynecology Hospital, Fudan University, and Shanghai Cancer Center, Fudan University.

Disclosure statement

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

Authors’ contributions

H.L. performed the study concept, design and acquisition; H.L., Y.H. and G.Z. obtained funding and study supervision; C.Z. and K.C. performed acquisition, analysis, and interpretation of data, and statistical analysis; J.L., M.Y., Y.W., and M.H. provided technical and material support; and all authors read and approved the final manuscript.

Data availability statement

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request. ScRNA-seq data for this article can be accessed online at https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE154600.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/2162402X.2023.2261242

Additional information

Funding

This study was funded by the National Natural Science Foundation of China grants 82072881 (HO Liu), 82273205 (HO Liu), and 82203665 (GD Zhang); Natural Science Foundation of Shanghai grant 20ZR1409000 (HO Liu); Shanghai Sailing Program grant 21YF1403900 (GD Zhang); Foundation of Science and Technology Commission of Shanghai Municipality 22Y31900502 (Y Huang); Shanghai Clinical Research Center for Gynecological Disease 22M1940200 (HO Liu); and Shanghai Urogenital System Disease Research Center 2022ZZ01012 (HO Liu). All study sponsors have no role in the study design, collection, analysis, and interpretation of data.