Prostate cancer (PCa) rarely responds to immune-checkpoint blockade (ICB) therapies. Cancer-associated fibroblasts (CAFs) are critical components of the immunologically "cold" tumor microenvironment and are considered a promising target to enhance the immunotherapy response. In this study, we aimed to reveal the mechanisms regulating CAF plasticity to identify potential strategies to switch CAFs from pro-tumorigenic to anti-tumor phenotypes and enhance ICB efficacy in PCa. Integration of four PCa single-cell RNA-sequencing datasets defined pro-tumorigenic and anti-tumor CAFs, and RNA-seq, flow cytometry, and a PCa organoid model demonstrated the functions of two CAF subtypes. Extracellular matrix-associated CAFs (ECM-CAF) promoted collagen deposition and cancer cell progression, and lymphocyte-associated CAFs (Lym-CAF) exhibited an anti-tumor phenotype and induced the infiltration and activation of CD8+ T cells. YAP1 activity regulated the ECM-CAF phenotype, and YAP1 silencing promoted switching to Lym-CAFs. NF-κB p65 was the core transcription factor in the Lym-CAF subset, and YAP1 inhibited nuclear translocation of p65. Selective depletion of YAP1 in ECM-CAFs in vivo promoted CD8+ T-cell infiltration and activation and enhanced the therapeutic effects of anti- PD-1 treatment in PCa. Overall, this study revealed a mechanism regulating CAF identity in PCa and highlighted a therapeutic strategy for altering the CAF subtype to suppress tumor growth and increase sensitivity to ICB.
Cancer research. 2024 Aug 13 [Epub ahead of print]
Hongtao Song, Tong Lu, Donghui Han, Jiayu Zhang, Lunbiao Gan, Chao Xu, Shaojie Liu, Peng Li, Keying Zhang, Zhihao Hu, Hongji Li, Yu Li, Xiaolong Zhao, Jingliang Zhang, Nianzeng Xing, Changhong Shi, Weihong Wen, Fa Yang, Weijun Qin
The Forth Military Medical University, Xian, China., Air Force Medical University, Xi'an, China., Air Force Medical University, China., Northwestern Polytechnical University, Xi'an, China., Air Force Medical University, Xi'an, Shaanxi, China., Air Force Medical University, Xi'an, Shaanxi Province China, China., Cancer Hospital of Chinese Academy of Medical Sciences, Beijing, China., Air Force Medical University, Xi'an, Shaan'xi, China., Northwestern Polytechnical University, Xi'an, Shaan'xi, China., Air Force Medical University, xi'an, Shaanxi Province China, China., Xijing Hospital, Xi'an, None Selected, China.