Activation of cGAS-STING in Bladder Cancer by Cisplatin Chemotherapy - Expert Commentary

Cisplatin is frequently used in neoadjuvant, adjuvant, and systemic therapy for advanced bladder cancer. A recent study by Fu et al. characterized the effects of cisplatin on cGAS-STING activation in bladder cancer. Cisplatin treatment of the T24 bladder cancer cell lines followed by RNA sequencing showed downstream enrichment of cGAS-STING signaling with higher transcription levels of NF-KB- and IRF3-related genes. Several bladder cancer cell lines in the CLE dataset had high expression levels of cGAS. In addition, markers of canonical STING activation, including the phosphorylated STING (Ser366), TBK (Ser173), and IRF3 (Ser396), were induced by cisplatin.

Using the immunocompetent MB49 mouse bladder cancer model, the authors show that cisplatin-induced cGAS-STING increased infiltration of CD8+ T cells and dendritic cells. This was associated with the accumulation of cytoplasmic double stranded DNA presumably due to leakage from the nucleus after cisplatin treatment and the formation of micronuclei.

This study highlights the potential cancer-cell autonomous and immune effects of cisplatin that are potentially mediated by cGAS-STING in bladder cancer. These findings have important implications for therapeutic approaches to combine chemotherapy and immunotherapy.

Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine, New York City, New York

References:

  1. Fu, G.; Wu, Y.; Zhao, G.; Chen, X.; Xu, Z.; Sun, J.; Tian, J.; Cheng, Z.; Shi, Y.; Jin, B. Activation of cGAS-STING Signal to Inhibit the Proliferation of Bladder Cancer: The Immune Effect of Cisplatin. Cells, 2022, 11, 3011. https://doi.org/10.3390/cells11193011
Read the Abstract
email news signup