Using CRISPR-Cas9, Siolas et al. engineered a gain-of-function Trp53R172H mutation in primary murine pancreatic ductal epithelial cells (PDEC) derived from KrasG12D mutation-harboring mice to decipher the immunosuppressive influence of a Trp53R172H mutation. Trp53R172H mutation led to a CXCL2-dependent increase in intratumoral CD11b+Ly6G+ neutrophils with a concomitant decrease in CD3+ T cells, CD8+ T cells, and Th1 helper cells, but not CD4+Foxp3+ regulatory T cells. Neutrophil depletion sensitized KrasG12D/+Trp53R172H/+ PDEC tumors to CD40 agonist plus gemcitabine and nab-paclitaxel chemotherapy combination.
Contributed by Shishir Pant
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.
Author Info: (1) Department of Medicine, New York University Grossman School of Medicine, New York, NY, USA; Laura and Isaac Perlmutter Cancer Center, New York University Grossman School of Med
Author Info: (1) Department of Medicine, New York University Grossman School of Medicine, New York, NY, USA; Laura and Isaac Perlmutter Cancer Center, New York University Grossman School of Medicine, New York, NY, USA. Electronic address: despina.siolas@nyulangone.org. (2) Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY, USA. (3) Molecular Oncology and Tumor Immunology Training Program, NYU Grossman School of Medicine, New York, NY, USA. (4) Department of Pathology, NYU Langone Health, New York, NY, USA. (5) Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY, USA. Electronic address: dafna.bar-sagi@nyulangone.org.
