Department of Medicine, University of Florida College of Medicine, Gainesville, Florida, USA.
Department of Surgery, University of Florida College of Medicine, Gainesville, Florida, USA.
Gut Microbes. 2022 Jan-Dec;14(1):2112881. doi: 10.1080/19490976.2022.2112881.
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 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 . SPF and ex-GF mice (reconstituted with SPF microbiota) developed larger PDAC tumors with decreased NK cell tumor infiltration and IFNγ expression versus GF-. Microbiota-induced PDAC tumorigenesis was attenuated by antibiotic exposure, a process reversed following NK cell depletion in both and C57BL/6 J mice. Compared to GF, SPF- 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.
临床前数据表明，肠道微生物群可以促进胰腺导管腺癌（PDAC），但其机制尚不清楚。我们假设肠道微生物群改变了抗肿瘤先天免疫反应，从而促进 PDAC 的进展。在抗生素耗尽微生物群后，将人 PDAC L3.6pl 细胞异种植入小鼠，而将同源小鼠 PDAC Pan02 细胞植入无菌（GF）C57BL/6J 小鼠的胰腺内。通过流式细胞术定量测定自然杀伤（NK）细胞及其 IFNγ 的表达。使用抗 Asialo GM1 抗体体内耗尽 NK 细胞，以确认 NK 细胞的作用。使用 SPF 和 GF 小鼠粪便的无细菌上清液来测试其对 NK-92MI 细胞抗肿瘤反应的影响。与 GF 相比，SPF 和 ex-GF 小鼠（用 SPF 微生物群重建）的 PDAC 肿瘤更大，NK 细胞肿瘤浸润和 IFNγ 表达减少。抗生素暴露可减弱微生物群诱导的 PDAC 肿瘤发生，在和 C57BL/6J 小鼠中，NK 细胞耗竭后可逆转这一过程。与 GF 相比，SPF-无生命粪便培养上清液抑制了 NK-92MI 的细胞毒性、迁移和抗癌相关基因的表达。肠道微生物群通过调节肿瘤内 NK 细胞的浸润和活性来促进 PDAC 肿瘤的进展。
