A cancer-neutrophil NETosis feedforward loop fueling chemo-resistant cancer stem cells 4491

Abstract Description Chemo immunotherapy has recently failed to demonstrate significant clinical benefits in patients with advanced bladder cancer, and the mechanisms underlying this suboptimal response remain elusive. Most studies have focused on tumor-intrinsic properties that render them “immune-excluded.” Our previous work reports immune-excluded murine muscle-invasive bladder cancer (MIBC) syngeneic models that exhibit intrinsic resistance to platinum-based chemotherapy and immune checkpoint inhibitor (ICI) therapy (PMID: 35347124). Here, we explore other potential resistance mechanisms in depth using scRNA-seq. We observed that chemoresistant tumors contain dominant neutrophil cell clusters in the tumor microenvironment (TME). These neutrophils are recruited by cancer stem cells into the TME, where they are transformed into pro-tumorigenic NETotic neutrophils and communicate back to cancer cells. This cancer-neutrophil NETosis feedforward loop fuels chemoresistant cancer stem cells. Based on CellChat analysis, we hypothesize that this communication is mediated by altered Plxnb2-Sema4d and Insr-Nampt signaling pathway interactions. The disruption of this interaction will improve the prognosis of immune-excluded bladder cancer. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)