期刊
GUT MICROBES
卷 14, 期 1, 页码 -出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/19490976.2022.2112881
关键词
Pancreatic cancer; pancreatic ductal adenocarcinoma; microbiome; immune response; natural killer cells
资金
- American Cancer Society Norma and Rich DiMarco Mentored Research Scholar Grant [MRSG-17-228-01-TBG]
- UF Health Cancer Center Pilot Project
- UF Health Cancer Center A1-Accelerator Grant
- NIH [R01DK073338]
- University of Florida Health Cancer Center Funds
- University of Florida Department of Medicine Gatorade Fund
This study demonstrates that the gut microbiota can promote the progression of PDAC tumors by modulating the activity and intra-tumoral infiltration of NK cells.
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 IFN gamma 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 IFN gamma 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.
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