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

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 IL1b is essential for the establishment of the protumorigenic PDA microenvironment. Tumor cell-derived IL1b 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 þ regulatory B cells, and Th17 cells. Loss of tumor cell-derived IL1 signaling in tumor stroma enabled intratumoral infiltration and activation of CD8 þ cytotoxic T cells, attenuated growth of pancreatic neoplasia, and conferred survival advantage to PDA-bearing mice. Accordingly, antibody-mediated neutralization of IL1b significantly enhanced the antitumor activity of a-PD-1 and was accompanied by increased tumor infiltration of CD8 þ T cells. Tumor cell expression of IL1b 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 IL1b 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 IL1b production by tumor cells through TLR4-NLRP3 inflammasome activation. Targeting this axis might provide an effective PDA therapeutic strategy.

Roles of IL-1 in Cancer: From Tumor Progression to Resistance to Targeted Therapies

“…In this regard, Kaplanov et al proved that a combined neutralization of IL-1β and PD-1 was responsible for an astonishing abrogation of tumor development in a mammary carcinoma murine model [61]. Similar results were obtained in a model of ductal pancreatic adenocarcinoma, in which IL-1β interception significantly enhances the antitumor activity of PD-1 blockade [62].…”

IL-20 antagonist suppresses PD-L1 expression and prolongs survival in pancreatic cancer models

“…A recent study demonstrated that the antibody-mediated neutralization of IL-1β significantly enhanced the antitumor activity of an anti-PD-1 antibody, which was accompanied by increased tumor infiltration by CD8 + T cells, indicating that targeting IL-1β has a beneficial effect on PDAC therapy outcomes 59 . We previously reported that IL-1β expression was upregulated by IL-20 in glioblastoma cells and oral cancer cells 30,35 .…”

The Immune Microenvironment in Pancreatic Cancer

“…For instance, IL-6 and its downstream effector STAT3 induce the differentiation of myeloid cells into immunosuppressive MDSCs or M2 TAMs. Furthermore, it negatively regulates neutrophils, natural killer cells, effector T cells, and dendritic cells (reviewed in [ 190 ]).…”