Gain-of-function p53 R172H 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 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.
Competing Interests: Declaration of interests D.S. is a consultant for Ciox Health and a shareholder in Mirimus. She served on a scientific advisory board for MabImmune and received royalties from Cold Spring Harbor Laboratory.
(Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)