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

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 KrasG12D-mutated mouse pancreatic ductal epithelial cells (PDECs) engineered genetically to express the Trp53(R172H) mutation with their p53wild-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.

Automated summary

Tumor genotype can influence the immune microenvironment in pancreatic cancer, leading to changes in immune cell populations and affecting treatment outcomes. Depletion of neutrophils in CRISPR Kras(G12D/+);Trp53(R172H/+) tumors can enhance the efficacy of CD40 immunotherapy and chemotherapy.