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Inhibition of JNK Signaling Overcomes Cancer-Associated Fibroblast-Mediated Immunosuppression and Enhances the Efficacy of Immunotherapy in Bladder Cancer
Cancer Research ( IF 12.5 ) Pub Date : 2024-09-18 , DOI: 10.1158/0008-5472.can-24-0940 Chengying Cui 1 , Haojie Zhang 2 , Congcong Yang 1 , Mingwei Yin 1 , Xinkun Teng 1 , Miaomiao Yang 3 , Dejie Kong 1 , Jinzhi Zhang 1 , Weidong Peng 4 , Zhimin Chu 1 , Jingjing Wang 1 , Yating Sun 1 , Liping Kang 1 , Bin Lyu 1 , Qian Gao 1 , Mingqing Wu 1 , Yongqiang Wang 5 , Yang Li 1
Cancer Research ( IF 12.5 ) Pub Date : 2024-09-18 , DOI: 10.1158/0008-5472.can-24-0940 Chengying Cui 1 , Haojie Zhang 2 , Congcong Yang 1 , Mingwei Yin 1 , Xinkun Teng 1 , Miaomiao Yang 3 , Dejie Kong 1 , Jinzhi Zhang 1 , Weidong Peng 4 , Zhimin Chu 1 , Jingjing Wang 1 , Yating Sun 1 , Liping Kang 1 , Bin Lyu 1 , Qian Gao 1 , Mingqing Wu 1 , Yongqiang Wang 5 , Yang Li 1
Affiliation
Currently, only 20-40% of cancer patients benefit from immune checkpoint inhibitors. Understanding the mechanisms underlying the immunosuppressive tumor microenvironment (TME) and characterizing dynamic changes in the immunological landscape during treatment are critical for improving responsiveness to immunotherapy. Here, we identified JNK signaling in cancer-associated fibroblasts (CAFs) as a regulator of the immunosuppressive tumor microenvironment. Single-cell RNA sequencing of bladder cancer treated with a JNK inhibitor revealed enhanced cytotoxicity and effector functions of CD8+ T cells. In untreated tumors, CAFs interacted frequently with CD8+ T cells and mediated their exhaustion. JNK inhibition abrogated the immunosuppression function of CAFs by downregulating the expression of TSLP, thereby restoring CD8+ T cell cytotoxicity. In addition, blockade of CAF-derived TSLP in combination with anti-PD1 treatment promoted tumor elimination by CD8+ T cells in vivo. Collectively, these results indicate that JNK signaling plays an important immunosuppressive role in the tumor microenvironment by promoting expression of TSLP in CAFs and suggest that inhibiting JNK signaling could be a promising immunotherapeutic strategy for cancer treatment.
中文翻译:
抑制 JNK 信号传导可克服癌症相关成纤维细胞介导的免疫抑制并增强膀胱癌免疫治疗的疗效
目前,只有 20-40% 的癌症患者受益于免疫检查点抑制剂。了解免疫抑制肿瘤微环境(TME)的机制并描述治疗期间免疫景观的动态变化对于提高免疫治疗的反应性至关重要。在这里,我们发现癌症相关成纤维细胞 (CAF) 中的 JNK 信号传导是免疫抑制肿瘤微环境的调节因子。用 JNK 抑制剂治疗的膀胱癌的单细胞 RNA 测序揭示了 CD8+ T 细胞的细胞毒性和效应功能增强。在未经治疗的肿瘤中,CAF 频繁与 CD8+ T 细胞相互作用并介导其耗竭。 JNK 抑制通过下调 TSLP 的表达来消除 CAF 的免疫抑制功能,从而恢复 CD8+ T 细胞的细胞毒性。此外,阻断 CAF 衍生的 TSLP 与抗 PD1 治疗相结合,可促进体内 CD8+ T 细胞消除肿瘤。总的来说,这些结果表明 JNK 信号通过促进 CAF 中 TSLP 的表达在肿瘤微环境中发挥重要的免疫抑制作用,并表明抑制 JNK 信号可能是一种有前途的癌症免疫治疗策略。
更新日期:2024-09-18
中文翻译:
抑制 JNK 信号传导可克服癌症相关成纤维细胞介导的免疫抑制并增强膀胱癌免疫治疗的疗效
目前,只有 20-40% 的癌症患者受益于免疫检查点抑制剂。了解免疫抑制肿瘤微环境(TME)的机制并描述治疗期间免疫景观的动态变化对于提高免疫治疗的反应性至关重要。在这里,我们发现癌症相关成纤维细胞 (CAF) 中的 JNK 信号传导是免疫抑制肿瘤微环境的调节因子。用 JNK 抑制剂治疗的膀胱癌的单细胞 RNA 测序揭示了 CD8+ T 细胞的细胞毒性和效应功能增强。在未经治疗的肿瘤中,CAF 频繁与 CD8+ T 细胞相互作用并介导其耗竭。 JNK 抑制通过下调 TSLP 的表达来消除 CAF 的免疫抑制功能,从而恢复 CD8+ T 细胞的细胞毒性。此外,阻断 CAF 衍生的 TSLP 与抗 PD1 治疗相结合,可促进体内 CD8+ T 细胞消除肿瘤。总的来说,这些结果表明 JNK 信号通过促进 CAF 中 TSLP 的表达在肿瘤微环境中发挥重要的免疫抑制作用,并表明抑制 JNK 信号可能是一种有前途的癌症免疫治疗策略。