Hu Ye, Recouvreux Maria Sol, Haro Marcela, Taylan Enes, Taylor-Harding Barbie, Walts Ann E, Karlan Beth Y, Orsulic Sandra
Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA.
Department of Gastroenterology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.
NPJ Precis Oncol. 2024 Feb 15;8(1):35. doi: 10.1038/s41698-024-00523-y.
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.
缺乏特异性生物标志物以及对不同类型的癌症相关成纤维细胞（CAFs）促进癌症进展的机制了解不足，阻碍了对CAFs的有效靶向治疗。虽然转化生长因子β（TGFβ）在CAFs中的作用已得到充分研究，但对一种结构和功能相似的蛋白质——激活素A（由INHBA编码）的关注较少。在这里，我们确定INHBA(+) CAFs是肿瘤促进和免疫抑制的关键参与者。对患者匹配的原发性、转移性和复发性卵巢癌的时空分析表明，富含INHBA(+) CAFs的侵袭性转移性肿瘤中也富含调节性T细胞（Tregs）。在卵巢癌小鼠模型中，腹腔注射激活素A中和抗体可减弱肿瘤进展，并减少促肿瘤成肌纤维细胞和巨噬细胞亚群的浸润。人卵巢CAFs中INHBA的下调抑制了促肿瘤CAF的功能。人卵巢CAFs与T细胞的共培养揭示了Treg分化对与INHBA(+) CAFs直接接触的依赖性。从机制上讲，CAFs中的INHBA/重组激活素A通过SMAD2依赖性信号传导诱导PD-L1的自分泌表达，从而促进Treg分化。总的来说，我们的研究确定了免疫调节性促肿瘤CAFs的INHBA(+)亚群是晚期卵巢癌潜在的治疗靶点，晚期卵巢癌通常对免疫治疗反应不佳。
