Pancreatic ductal adenocarcinoma (PDA) is an aggressive malignancy typified by a highly stromal and weakly immunogenic tumor microenvironment that promotes tumor evolution and contributes to therapeutic resistance. Here, we demonstrate that PDA tumor cell-derived proinflammatory cytokine IL1β is essential for the establishment of the protumorigenic PDA microenvironment. Tumor cell-derived IL1β promoted the activation and secretory phenotype of quiescent pancreatic stellate cells and established an immunosuppressive milieu mediated by M2 macrophages, myeloid-derived suppressor cells, CD1dhiCD5+ regulatory B cells, and Th17 cells. Loss of tumor cell-derived IL1 signaling in tumor stroma enabled intratumoral infiltration and activation of CD8+ cytotoxic T cells, attenuated growth of pancreatic neoplasia, and conferred survival advantage to PDA-bearing mice. Accordingly, antibody-mediated neutralization of IL1β significantly enhanced the antitumor activity of α-PD-1 and was accompanied by increased tumor infiltration of CD8+ T cells. Tumor cell expression of IL1β in vivo was driven by microbial-dependent activation of toll-like receptor 4 (TLR4) signaling and subsequent engagement of the NLRP3 inflammasome. Collectively, these findings identify a hitherto unappreciated role for tumor cell-derived IL1β in orchestrating an immune-modulatory program that supports pancreatic tumorigenesis. SIGNIFICANCE: These findings identify a new modality for immune evasion in PDA that depends on IL1β production by tumor cells through TLR4-NLRP3 inflammasome activation. Targeting this axis might provide an effective PDA therapeutic strategy.

中文翻译：

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肿瘤细胞衍生的 IL1β 促进胰腺癌中的结缔组织形成和免疫抑制。

胰腺导管腺癌（PDA）是一种侵袭性恶性肿瘤，其特征是高度基质和弱免疫原性的肿瘤微环境，可促进肿瘤进化并导致治疗耐药。在这里，我们证明 PDA 肿瘤细胞衍生的促炎细胞因子 IL1β 对于建立促肿瘤 PDA 微环境至关重要。肿瘤细胞来源的 IL1β 促进静止胰腺星状细胞的激活和分泌表型，并建立由 M2 巨噬细胞、骨髓源性抑制细胞、CD1dhiCD5+ 调节性 B 细胞和 Th17 细胞介导的免疫抑制环境。肿瘤基质中肿瘤细胞衍生的 IL1 信号传导的缺失导致肿瘤内浸润并激活 CD8+ 细胞毒性 T 细胞，减弱胰腺肿瘤的生长，并赋予携带 PDA 的小鼠生存优势。因此，抗体介导的 IL1β 中和显着增强了 α-PD-1 的抗肿瘤活性，并伴随着 CD8+ T 细胞的肿瘤浸润增加。IL1β 体内肿瘤细胞表达是由微生物依赖性 Toll 样受体 4 (TLR4) 信号传导激活以及随后 NLRP3 炎性体的参与驱动的。总的来说，这些发现确定了肿瘤细胞衍生的 IL1β 在协调支持胰腺肿瘤发生的免疫调节程序中的迄今为止未被认识到的作用。意义：这些发现确定了 PDA 免疫逃避的新方式，该方式依赖于肿瘤细胞通过 TLR4-NLRP3 炎性体激活产生 IL1β。针对该轴可能提供有效的 PDA 治疗策略。