The Pancreatic Cancer Microbiome Promotes Oncogenesis by Induction of Innate and Adaptive Immune Suppression.
The Pancreatic Cancer Microbiome Promotes Oncogenesis by Induction of Innate and Adaptive Immune Suppression.
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DOI：
10.1158/2159-8290.cd-17-1134
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发表时间：
2018-04
期刊：
影响因子：
28.2
通讯作者：
Miller G
中科院分区：
文献类型：
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作者：
Pushalkar S;Hundeyin M;Daley D;Zambirinis CP;Kurz E;Mishra A;Mohan N;Aykut B;Usyk M;Torres LE;Werba G;Zhang K;Guo Y;Li Q;Akkad N;Lall S;Wadowski B;Gutierrez J;Kochen Rossi JA;Herzog JW;Diskin B;Torres-Hernandez A;Leinwand J;Wang W;Taunk PS;Savadkar S;Janal M;Saxena A;Li X;Cohen D;Sartor RB;Saxena D;Miller G
我们发现，与小鼠和人类的正常胰腺相比，癌性胰腺含有明显更丰富的微生物组，而与肠道相比，肿瘤胰腺中的选定细菌差异增加。微生物组的消融可防止预侵入性和侵入性PDA，而从携带PDA的宿主转移细菌（而不是对照）可逆转肿瘤保护。细菌消融与PDA肿瘤微环境的免疫原性重编程相关，包括髓源性抑制细胞减少和M1巨噬细胞分化增加，促进CD 4 + T细胞的Th 1分化和CD 8 + T细胞活化。细菌消融还通过上调PD-1表达实现了检查点靶向免疫疗法的功效。从机制上讲，PDA微生物组通过差异激活单核细胞中的选择性toll样受体来产生致耐受性免疫程序。这些数据表明，内源性微生物群促进PDA的致残性免疫抑制特征，并且微生物群具有作为调节疾病进展的治疗靶点的潜力。
We found that the cancerous pancreas harbors a markedly more abundant microbiome compared to normal pancreas in both mice and humans, while select bacteria are differentially increased in the tumorous pancreas compared to gut. Ablation of the microbiome protects against pre-invasive and invasive PDA, whereas transfer of bacteria from PDA-bearing hosts, but not controls, reverses tumor-protection. Bacterial ablation was associated with immunogenic reprogramming of the PDA tumor microenvironment including a reduction in myeloid-derived suppressor cells and an increase in M1 macrophage differentiation, promoting Th1 differentiation of CD4+ T cells and CD8+ T cell activation. Bacterial ablation also enabled efficacy for checkpoint-targeted immunotherapy by upregulating PD-1 expression. Mechanistically, the PDA microbiome generated a tolerogenic immune program by differentially activating select toll-like receptors in monocytic cells. These data suggest that endogenous microbiota promote the crippling immune-suppression characteristic of PDA and that the microbiome has potential as a therapeutic target in the modulation of disease progression.