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- W4361824743 abstract "<div>Abstract<p>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, CD1d<sup>hi</sup>CD5<sup>+</sup> regulatory B cells, and Th17 cells. Loss of tumor cell–derived IL1 signaling in tumor stroma enabled intratumoral infiltration and activation of CD8<sup>+</sup> 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<sup>+</sup> T cells. Tumor cell expression of IL1β <i>in vivo</i> 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.</p>Significance:<p>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.</p></div>" @default.
- W4361824743 created "2023-04-05" @default.
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- W4361824743 date "2023-03-31" @default.
- W4361824743 modified "2023-10-17" @default.
- W4361824743 title "Data from Tumor Cell–Derived IL1β Promotes Desmoplasia and Immune Suppression in Pancreatic Cancer" @default.
- W4361824743 doi "https://doi.org/10.1158/0008-5472.c.6512155.v1" @default.
- W4361824743 hasPublicationYear "2023" @default.
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