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.

中文翻译：

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YAP1 抑制诱导前列腺癌相关成纤维细胞表型转换为肿瘤抑制


前列腺癌 （PCa） 很少对免疫检查点阻断 （ICB） 疗法有反应。癌症相关成纤维细胞 （CAF） 是免疫学上“冷”肿瘤微环境的关键组成部分，被认为是增强免疫治疗反应的有前途的靶标。在这项研究中，我们旨在揭示调节 CAF 可塑性的机制，以确定将 CAFs 从促肿瘤表型转变为抗肿瘤表型并增强 PCa 中 ICB 疗效的潜在策略。整合四个 PCa 单细胞 RNA 测序数据集定义了促肿瘤和抗肿瘤 CAFs，RNA-seq、流式细胞术和 PCa 类器官模型证明了两种 CAF 亚型的功能。细胞外基质相关 CAFs （ECM-CAF） 促进胶原沉积和癌细胞进展，淋巴细胞相关 CAFs （Lym-CAF） 表现出抗肿瘤表型并诱导 CD8+ T 细胞的浸润和活化。YAP1 活性调节 ECM-CAF 表型，YAP1 沉默促进向 Lym-CAFs 的转换。NF-κB p65 是 Lym-CAF 亚群中的核心转录因子，YAP1 抑制 p65 的核易位。体内 ECM-CAFs 中 YAP1 的选择性耗竭促进了 CD8+ T 细胞浸润和活化，并增强了 PCa 中抗 PD-1 治疗的治疗效果。总体而言，这项研究揭示了调节 PCa 中 CAF 身份的机制，并强调了一种改变 CAF 亚型以抑制肿瘤生长和增加对 ICB 敏感性的治疗策略。