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

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.