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

Summary 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 p53R172H 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 p53R172H. Mechanistically, we show that p53R172H associates with the distal enhancers of the Cxcl1 gene, increasing enhancer activity and Cxcl1 expression. p53R172H occupies these enhancers in an NF-κB-pathway-dependent manner, suggesting NF-κB’s role in recruiting p53R172H to the Cxcl1 enhancers. Our work uncovers how a common mutation in a tumor-suppressor transcription factor appropriates enhancers, stimulating chemokine expression and establishing an immunosuppressive TME that diminishes ICI efficacy in PDAC. Graphical Abstract Competing Interest Statement R.K.J. is a Consultant for Accurius, DynamiCure, and SynDevRx; owns equity in Accurius, Enlight, and SynDevRx; served on the Board of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund, Tekla World Healthcare Fund and received a research Grant from Sanofi. No funding or reagents from these organizations were used in this study. S.S. is an SAB member for Related Sciences, Arcus Biosciences, Ankyra Therapeutics, Prox Bio, and Repertoire Immune Medicines. S.S. is a co-founder of Danger Bio. S.S. is a consultant for TAKEDA and Merck and receives funding for unrelated projects from Leap Therapeutics and iTeos Therapeutics. S.S. interests are reviewed and managed under MIT policies for potential conflicts of interest.