Tumor Cell-Derived IL1β Promotes Desmoplasia and Immune Suppression in Pancreatic Cancer

Cancer Res. 2020 Mar 1;80(5):1088-1101. doi: 10.1158/0008-5472.CAN-19-2080. Epub 2020 Jan 8.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Immunological / pharmacology
  • Antineoplastic Agents, Immunological / therapeutic use
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • Carcinogenesis / immunology*
  • Carcinoma, Pancreatic Ductal / drug therapy
  • Carcinoma, Pancreatic Ductal / immunology*
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Line, Tumor / transplantation
  • Disease Models, Animal
  • Drug Synergism
  • Epithelial Cells
  • Female
  • Humans
  • Inflammasomes / immunology
  • Inflammasomes / metabolism
  • Interleukin-1beta / antagonists & inhibitors
  • Interleukin-1beta / immunology
  • Interleukin-1beta / metabolism*
  • Lymphocytes, Tumor-Infiltrating / drug effects
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Mice
  • Mice, Transgenic
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
  • Pancreatic Ducts / cytology
  • Pancreatic Neoplasms / drug therapy
  • Pancreatic Neoplasms / immunology*
  • Pancreatic Neoplasms / pathology
  • Primary Cell Culture
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Programmed Cell Death 1 Receptor / immunology
  • Signal Transduction / immunology
  • Toll-Like Receptor 4 / metabolism
  • Tumor Escape / drug effects
  • Tumor Escape / immunology*
  • Tumor Microenvironment / drug effects
  • Tumor Microenvironment / immunology


  • Antineoplastic Agents, Immunological
  • IL1B protein, human
  • IL1B protein, mouse
  • Inflammasomes
  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • Nlrp3 protein, mouse
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • TLR4 protein, human
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4