A Distinct Gut Microbial Ecology is Associated with Enhanced Chemosensitivity Following Neutrophil Attenuation in Pancreatic Cancer

Abstract

Background: Infiltration of innate immune cells, such as neutrophils, in the tumor microenvironment (TME) are associated with worse oncologic outcomes in pancreatic ductal adenocarcinoma (PDAC). Given recent evidence highlighting the complex intersection between chemosensitivity and the gut microbiome in solid tumors, we sought to investigate if the enhanced chemosensitivity observed with neutrophil attenuation in PDAC is associated with a distinct gut microbial ecology. Methods: C57BL/6 mice were orthotopically injected with syngeneic KrasG12D/+;Trp53fl/+;Pdx-Cre(KPC) PDAC cells, and randomized into four treatment groups after 10d tumor growth (n=8-10/arm): vehicle-control, anti-Ly6G antibody treatment alone with neutrophil-attenuating—but not depleting—dosing (25 μg/dose) q3d, gemcitabine(100 mg/kg) and paclitaxel(10 mg/kg) qwk(G/P), and G/P+anti-Ly6G. Fecal samples from mice (n=3/group) were collected 10d after treatment and submitted for shotgun metagenomic sequencing. Results: Bray-Curtis principal coordinate analysis of microbial β-diversity revealed significant differences in microbial composition with neutrophil attenuation and chemotherapy. Abundance of 37 species were differentially significant between G/P+anti-Ly6G and G/P-treated cohorts (p-adj<0.05). Seven Alistipes spp. (class Bacteroidea)—previously associated with chemoresistance in solid cancers—were significantly reduced in the gut microbiome of G/P+anti-Ly6G-treated mice. Bifidobacterium pseudolongum, previously associated with PDAC tumor progression, was the most significantly reduced bacterial species in the gut microbiome of G/P+anti-Ly6G-treated mice when compared with G/P alone-group. Conclusion: Our data unearth potential crosstalk between a distinct but narrow gut microbial ecology and anti-tumor adaptive immunity in response to neutrophil attenuation that is associated with improved chemosensitivity in PDAC. Therapeutic manipulation of this microbial program may mitigate chemoresistance and improve outcomes in PDAC patients.