We found that the cancerous pancreas harbors a markedly more abundant microbiome compared with normal pancreas in both mice and humans, and select bacteria are differentially increased in the tumorous pancreas compared with gut. Ablation of the microbiome protects against preinvasive and invasive pancreatic ductal adenocarcinoma (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.Significance: We found that a distinct and abundant microbiome drives suppressive monocytic cellular differentiation in pancreatic cancer via selective Toll-like receptor ligation leading to T-cell anergy. Targeting the microbiome protects against oncogenesis, reverses intratumoral immune tolerance, and enables efficacy for checkpoint-based immunotherapy. These data have implications for understanding immune suppression in pancreatic cancer and its reversal in the clinic. Cancer Discov; 8(4); 403-16. ©2018 AACR.See related commentary by Riquelme et al., p. 386This article is highlighted in the In This Issue feature, p. 371.

中文翻译：

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胰腺癌微生物组通过诱导先天性和适应性免疫抑制促进肿瘤发生。


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，并且与肠道相比，癌性胰腺中的特定细菌有差异性增加。微生物群的消融可预防侵袭前和侵袭性胰腺导管腺癌 (PDA)，而从携带 PDA 的宿主（而非对照）转移细菌会逆转肿瘤保护作用。细菌消融与 PDA 肿瘤微环境的免疫原性重编程相关，包括骨髓源性抑制细胞的减少和 M1 巨噬细胞分化的增加，促进 CD4+ T 细胞的 TH1 分化和 CD8+ T 细胞的激活。细菌消融还通过上调 PD-1 表达来实现检查点靶向免疫疗法的功效。从机制上讲，PDA 微生物组通过差异性激活单核细胞中的选择性 Toll 样受体来产生耐受性免疫程序。这些数据表明，内源性微生物群促进了 PDA 的严重免疫抑制特征，并且微生物组具有作为调节疾病进展的治疗靶点的潜力。意义：我们发现独特且丰富的微生物组驱动胰腺癌中的抑制性单核细胞分化通过选择性 Toll 样受体连接导致 T 细胞无反应性。针对微生物组可以防止肿瘤发生，逆转瘤内免疫耐受，并使基于检查点的免疫疗法发挥功效。这些数据对于了解胰腺癌的免疫抑制及其在临床中的逆转具有重要意义。癌症发现； 8(4)； 403-16。 ©2018 AACR。请参阅 Riquelme 等人的相关评论，第 14 页。 386这篇文章在本期特稿中突出显示，第 386 页。 371.