2. Academic Validation
  3. Inhibition of JNK Signaling Overcomes Cancer-Associated Fibroblast-Mediated Immunosuppression and Enhances the Efficacy of Immunotherapy in Bladder Cancer

Inhibition of JNK Signaling Overcomes Cancer-Associated Fibroblast-Mediated Immunosuppression and Enhances the Efficacy of Immunotherapy in Bladder Cancer

  • Cancer Res. 2024 Dec 16;84(24):4199-4213. doi: 10.1158/0008-5472.CAN-24-0940.
Chengying Cui # 1,  Haojie Zhang # 2,  Congcong Yang 1,  Mingwei Yin 1 3,  Xinkun Teng 1,  Miaomiao Yang 4 5,  Dejie Kong 1,  Jinzhi Zhang 1,  Weidong Peng 6,  Zhimin Chu 1,  Jingjing Wang 1,  Yating Sun 1,  Liping Kang 1,  Bin Lyu 1,  Qian Gao 1,  Mingqing Wu 1,  Yongqiang Wang 7,  Yang Li 1 8
Affiliations

Affiliations

  • 1 Department of Genetics, School of Life Science, Anhui Medical University, Hefei, China.
  • 2 Department of Urology, Huadong Hospital, Fudan University, Shanghai, China.
  • 3 Department of Pathophysiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China.
  • 4 The First Affiliated Hospital of Anhui Medical University, Pathology Center, Hefei, China.
  • 5 Anhui Public Health Clinical Center, Pathology Center, Hefei, China.
  • 6 Department of Epidemiology and Health Statistics, School of Public Health, Anhui Medical University, Hefei, China.
  • 7 Department of Urology, South China Hospital, Medical School, Shenzhen University, Shenzhen, China.
  • 8 Anhui Province Key Laboratory of Urological and Andrological Diseases Research and Medical Transformation, Anhui Medical University, Hefei, China.
  • # Contributed equally.
PMID: 39292817 DOI: 10.1158/0008-5472.CAN-24-0940
Abstract

Currently, only 20% to 40% of patients with Cancer benefit from immune checkpoint inhibitors. Understanding the mechanisms underlying the immunosuppressive tumor microenvironment (TME) and characterizing dynamic changes in the immunologic landscape during treatment are critical for improving responsiveness to immunotherapy. In this study, we identified JNK signaling in cancer-associated fibroblasts (CAF) as a regulator of the immunosuppressive TME. Single-cell RNA Sequencing of bladder Cancer samples 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 thymic stromal lymphopoietin (TSLP), thereby restoring CD8+ T-cell cytotoxicity. In addition, blockade of CAF-derived TSLP in combination with anti-PD-1 treatment promoted tumor elimination by CD8+ T cells in vivo. Collectively, these results indicate that JNK signaling plays an important immunosuppressive role in the TME by promoting expression of TSLP in CAFs and suggest that inhibiting JNK signaling could be a promising immunotherapeutic strategy for Cancer treatment. Significance: JNK signaling promotes the secretion of TSLP by bladder cancer-associated fibroblasts to impede CD8+ T-cell activity, which can be circumvented by combination treatment targeting JNK signaling and PD-1.

Figures
Products
Inhibitors & Agonists
Other Products