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Mutant-p53 stimulates Cxcl1 Expression from Distal Enhancers to Suppress Immune Response to Pancreatic Cancer [PRO-seq]

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 alter cell-intrinsic gene programs to influence the immune landscape of the tumor microenvironment (TME) remains poorly understood. Here, we demonstrate that p53R172H enhances tumor growth, establishes a suppressive TME by inducing immune evasion, and blunts the effectiveness of immune checkpoint inhibitors (ICIs). We discovered that the oncogenic function of p53R172H is mediated by upregulation of the immunosuppressive chemokine Cxcl1. Mechanistically, we show that p53R172H binds to the distal enhancers of the Cxcl1 gene and increases enhancer activity and Cxcl1 expression. NF-kB also occupies Cxcl1 enhancers, and p53R172H binds these enhancers in an NF-kB-dependent manner, suggesting a role of NF-kB in commuting p53R172H to the Cxcl1 enhancers. Our findings elucidate how a common mutation in a critical tumor-suppressor gene exploits enhancers to modulate chemokine gene expression and foster an immunosuppressive TME in PDAC that undermines the efficacy of ICI.

ORGANISM(S): Mus musculus

PROVIDER: GSE275106 | GEO | 2024/10/09

REPOSITORIES: GEO

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Project description:Immunotherapeutics represent highly promising agents with the potential to improve patient outcomes in a variety of cancer types. Unfortunately, single-agent immunotherapy has achieved limited clinical benefit to date in patients suffering from pancreatic ductal adenocarcinoma (PDAC). This may be due to the presence of a uniquely immunosuppressive tumor microenvironment (TME) present in PDACs, which creates a barrier to effective immune surveillance. Critical obstacles to immunotherapy in PDAC tumors include the dense desmoplastic stroma that acts as a barrier to T-cell infiltration and the high numbers of tumor-associated immunosuppressive cells. We have identified hyperactivated focal adhesion kinase (FAK) activity in neoplastic PDAC cells as a significant regulator of the fibrotic and immunosuppressive TME. We found that FAK activity was elevated in human PDAC tissues and correlates with high levels of fibrosis and poor CD8+ cytotoxic T-cell infiltration. Single-agent FAK inhibition (VS-4718) dramatically limited tumor progression, resulting in a doubling of survival in the p48-Cre/LSL-KrasG12D/p53Flox/+ (KPC) mouse model of human PDAC. This alteration in tumor progression was associated with dramatically reduced tumor fibrosis, decreased numbers of tumor-infiltrating immature myeloid cells and immunosuppressive macrophages. We postulated that these desirable effects of FAK inhibition on the TME might render PDAC tumors more sensitive to immunotherapy. Accordingly, we found that VS-4718 rendered the previously unresponsive KPC mouse model responsive to anti-PD1 and anti-CTLA4 antagonists leading to a nearly tripling of survival times. These data suggest that FAK inhibition increases immune surveillance by overcoming the fibrotic and immunosuppressive PDAC TME thus rendering tumors more responsive to immunotherapy. We treated KP orthotopic tumor-bearing mice with vehicle and FAK inhibitor (FAKi) for 14 days, then extracted total RNA from tumor tissues.

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Mutant-p53 stimulates Cxcl1 Expression from Distal Enhancers to Suppress Immune Response to Pancreatic Cancer [PRO-seq]

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