Tumor Cell-Derived IL1ß Promotes Desmoplasia and Immune Suppression in Pancreatic Cancer.
Cancer Res
; 80(5): 1088-1101, 2020 03 01.
Article
en En
| MEDLINE
| ID: mdl-31915130
ABSTRACT
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 IL1ß is essential for the establishment of the protumorigenic PDA microenvironment. Tumor cell-derived IL1ß 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 IL1ß significantly enhanced the antitumor activity of α-PD-1 and was accompanied by increased tumor infiltration of CD8+ T cells. Tumor cell expression of IL1ß 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 IL1ß 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 IL1ß production by tumor cells through TLR4-NLRP3 inflammasome activation. Targeting this axis might provide an effective PDA therapeutic strategy.
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Neoplasias Pancreáticas
/
Escape del Tumor
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Carcinoma Ductal Pancreático
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Interleucina-1beta
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Carcinogénesis
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Cancer Res
Año:
2020
Tipo del documento:
Article