Intestinal microbiota modulates pancreatic carcinogenesis through intratumoral natural killer cells.
Intestinal microbiota modulates pancreatic carcinogenesis through intratumoral natural killer cells.
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DOI：
10.1080/19490976.2022.2112881
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发表时间：
2022-01
期刊：
影响因子：
12.2
通讯作者：
Thomas, Ryan M.
中科院分区：
文献类型：
--
作者：
Yu, Qin;Newsome, Rachel C.;Beveridge, Mark;Hernandez, Maria C.;Gharaibeh, Raad Z.;Jobin, Christian;Thomas, Ryan M.
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.
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