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

Cell Rep. 2021 Aug 24;36(8):109578. doi: 10.1016/j.celrep.2021.109578.

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 KrasG12D-mutated mouse pancreatic ductal epithelial cells (PDECs) engineered genetically to express the Trp53R172H mutation with their p53 wild-type control. KrasG12D/+;Trp53R172H/+ 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 KrasG12D/+;Trp53R172H/+ PDEC tumors reverses the neutrophil phenotype. Neutrophil depletion of mice bearing CRISPR KrasG12D/+;Trp53R172H/+ tumors augments sensitivity to combined CD40 immunotherapy and chemotherapy. These data link Trp53R172H to the presence of intratumoral neutrophils in pancreatic cancer and suggest that tumor genotypes could inform selection of affected individuals for immunotherapy.

Keywords: immune microenvironment; mutant p53; neutrophils; pancreatic cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Pancreatic Ductal* / genetics
  • Carcinoma, Pancreatic Ductal* / immunology
  • Carcinoma, Pancreatic Ductal* / therapy
  • Gain of Function Mutation*
  • Immunotherapy*
  • Mice
  • Mice, Transgenic
  • Neutrophil Infiltration / genetics*
  • Neutrophils / immunology*
  • Pancreatic Neoplasms* / genetics
  • Pancreatic Neoplasms* / immunology
  • Pancreatic Neoplasms* / therapy
  • Th1 Cells
  • Tumor Suppressor Protein p53* / genetics
  • Tumor Suppressor Protein p53* / immunology

Substances

  • Trp53 protein, mouse
  • Tumor Suppressor Protein p53