Gain-of-function p53R172H mutation drives accumulation of neutrophils in pancreatic tumors, promoting resistance to immunotherapy

Abstract

Tumor genotype can influence the immune microenvironment, which plays a critical role in cancer development and therapy resistance. However, the immune effects of gain-of-function Trp53 mutations have not been defined in pancreatic cancer. We compare the immune profiles generated by Kras^G12D-mutated mouse pancreatic ductal epithelial cells (PDECs) engineered genetically to express the Trp53^R172H mutation with their p53 wild-type control. Kras^G12D/+;Trp53^R172H/+ tumors have a distinct immune profile characterized by an influx of CD11b⁺Ly6G⁺ neutrophils and concomitant decreases in CD3⁺ T cells, CD8⁺ T cells, and CD4⁺ T helper 1 cells. Knockdown of CXCL2, a neutrophil chemokine, in the tumor epithelial compartment of CRISPR Kras^G12D/+;Trp53^R172H/+ PDEC tumors reverses the neutrophil phenotype. Neutrophil depletion of mice bearing CRISPR Kras^G12D/+;Trp53^R172H/+ tumors augments sensitivity to combined CD40 immunotherapy and chemotherapy. These data link Trp53^R172H to the presence of intratumoral neutrophils in pancreatic cancer and suggest that tumor genotypes could inform selection of affected individuals for immunotherapy.