期刊
CANCER RESEARCH
卷 80, 期 5, 页码 1088-1101出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-19-2080
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资金
- NIH/National Cancer Institute [P30CA016087]
- NIH/NCI grant [CA210263]
- Stand Up To Cancer-Lustgarten Foundation Pancreatic Cancer Convergence Dream Team Name Translational Research Grant [SU2C-AACR-DT14-14]
- NIH [T32GM115313]
- Canadian Institutes of Health Research Fellowship [146792]
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 IL1 beta is essential for the establishment of the protumorigenic PDA microenvironment. Tumor cell-derived IL1 beta 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(hi)CD5(+) 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 IL1 beta significantly enhanced the antitumor activity of alpha-PD-1 and was accompanied by increased tumor infiltration of CD8(+) T cells. Tumor cell expression of IL1 beta 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 IL1 beta 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 IL1 beta production by tumor cells through TLR4-NLRP3 inflammasome activation. Targeting this axis might provide an effective PDA therapeutic strategy.
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