Mutant p53 Exploits Enhancers to Elevate Immunosuppressive Chemokine Expression and Impair Immune Checkpoint Inhibitors in Pancreatic Cancer.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer without effective treatments. It is characterized by activating KRAS mutations and p53 alterations. However, how these mutations dysregulate cancer-cell-intrinsic gene programs to influence the immune landscape of the tumor microenvironment (TME) remains poorly understood. Here, we show that p53^R172H establishes an immunosuppressive TME, diminishes the efficacy of immune checkpoint inhibitors (ICIs), and enhances tumor growth. Our findings reveal that the upregulation of the immunosuppressive chemokine Cxcl1 mediates these pro-tumorigenic functions of p53^R172H. Mechanistically, we show that p53^R172H associates with the distal enhancers of the Cxcl1 gene, increasing enhancer activity and Cxcl1 e

SUBMITTER: Mahat DB 

PROVIDER: S-EPMC11383995 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature