INHBA(+) cancer-associated fibroblasts generate an immunosuppressive tumor microenvironment in ovarian cancer

Ye Hu; Maria Sol Recouvreux; Marcela Haro; Enes Taylan; Barbie Taylor-Harding; Ann E Walts; Beth Y Karlan; Sandra Orsulic

doi:10.1038/s41698-024-00523-y

INHBA(+) cancer-associated fibroblasts generate an immunosuppressive tumor microenvironment in ovarian cancer

NPJ Precis Oncol. 2024 Feb 15;8(1):35. doi: 10.1038/s41698-024-00523-y.

Authors

Ye Hu^{1

2}, Maria Sol Recouvreux¹, Marcela Haro³, Enes Taylan¹, Barbie Taylor-Harding¹, Ann E Walts⁴, Beth Y Karlan^{1

5}, Sandra Orsulic^{6

7

8

9}

Affiliations

¹ Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA.
² Department of Gastroenterology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.
³ Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
⁴ Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
⁵ Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, 90095, USA.
⁶ Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA. SOrsulic@mednet.ucla.edu.
⁷ Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, 90095, USA. SOrsulic@mednet.ucla.edu.
⁸ Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA. SOrsulic@mednet.ucla.edu.
⁹ United States Department of Veterans Affairs, Greater Los Angeles Healthcare System, Los Angeles, CA, 90073, USA. SOrsulic@mednet.ucla.edu.

Abstract

Effective targeting of cancer-associated fibroblasts (CAFs) is hindered by the lack of specific biomarkers and a poor understanding of the mechanisms by which different populations of CAFs contribute to cancer progression. While the role of TGFβ in CAFs is well-studied, less attention has been focused on a structurally and functionally similar protein, Activin A (encoded by INHBA). Here, we identified INHBA(+) CAFs as key players in tumor promotion and immunosuppression. Spatiotemporal analyses of patient-matched primary, metastatic, and recurrent ovarian carcinomas revealed that aggressive metastatic tumors enriched in INHBA(+) CAFs were also enriched in regulatory T cells (Tregs). In ovarian cancer mouse models, intraperitoneal injection of the Activin A neutralizing antibody attenuated tumor progression and infiltration with pro-tumorigenic subsets of myofibroblasts and macrophages. Downregulation of INHBA in human ovarian CAFs inhibited pro-tumorigenic CAF functions. Co-culture of human ovarian CAFs and T cells revealed the dependence of Treg differentiation on direct contact with INHBA(+) CAFs. Mechanistically, INHBA/recombinant Activin A in CAFs induced the autocrine expression of PD-L1 through SMAD2-dependent signaling, which promoted Treg differentiation. Collectively, our study identified an INHBA(+) subset of immunomodulatory pro-tumoral CAFs as a potential therapeutic target in advanced ovarian cancers which typically show a poor response to immunotherapy.

Abstract

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