Intestinal microbiota modulates pancreatic carcinogenesis through intratumoral natural killer cells

Gut Microbes. 2022 Jan-Dec;14(1):2112881. doi: 10.1080/19490976.2022.2112881.

Abstract

Preclinical data demonstrate that the gut microbiota can promote pancreatic ductal adenocarcinoma (PDAC), but mechanisms remain unclear. We hypothesized that intestinal microbiota alters anti-tumor innate immunity response to facilitate PDAC progression. Human PDAC L3.6pl cells were heterotopically implanted into Rag1-/- mice after microbiota depletion with antibiotics, while syngeneic murine PDAC Pan02 cells were implanted intrapancreatic into germ-free (GF) C57BL/6 J mice. Natural killer (NK) cells and their IFNγ expression were quantitated by flow cytometry. NK cells were depleted in vivo using anti-Asialo GM1 antibody to confirm the role of NK cells. Bacteria-free supernatant from SPF and GF mice feces was used to test its effect on NK-92MI cell anti-tumor response in vitro. SPF and ex-GF mice (reconstituted with SPF microbiota) developed larger PDAC tumors with decreased NK cell tumor infiltration and IFNγ expression versus GF-Rag1-/-. Microbiota-induced PDAC tumorigenesis was attenuated by antibiotic exposure, a process reversed following NK cell depletion in both Rag1-/- and C57BL/6 J mice. Compared to GF, SPF-Rag1-/- abiotic stool culture supernatant inhibited NK-92MI cytotoxicity, migration, and anti-cancer related gene expression. Gut microbiota promotes PDAC tumor progression through modulation of the intratumoral infiltration and activity of NK cells.

Keywords: Pancreatic cancer; immune response; microbiome; natural killer cells; pancreatic ductal adenocarcinoma.

Publication types

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

MeSH terms

  • Animals
  • Carcinogenesis
  • Carcinoma, Pancreatic Ductal* / pathology
  • Gastrointestinal Microbiome*
  • Homeodomain Proteins / genetics
  • Humans
  • Killer Cells, Natural
  • Mice
  • Mice, Inbred C57BL
  • Pancreatic Neoplasms* / pathology

Substances

  • Homeodomain Proteins

Supplementary concepts

  • Pancreatic Carcinoma