Inflammasomes are key regulators of innate immunity in chronic inflammatory disorders and
autoimmune diseases, but their role in
inflammation-associated
tumorigenesis remains ill-defined. Here we reveal a protumorigenic role in
gastric cancer for the key
inflammasome adaptor apoptosis-related speck-like
protein containing a CARD (ASC) and its effector
cytokine IL18. Genetic ablation of ASC in the gp130F/F spontaneous mouse model of intestinal-type
gastric cancer suppressed
tumorigenesis by augmenting caspase-8-like apoptosis in the gastric epithelium, independently from effects on myeloid cells and mucosal
inflammation. This phenotype was characterized by reduced activation of caspase-1 and NF-κB activation and reduced expression of mature
IL18, but not IL1β, in gastric
tumors. Genetic ablation of
IL18 in the same model also suppressed gastric
tumorigenesis, whereas blockade of IL1β and IL1α activity upon genetic ablation of the
IL1 receptor had no effect. The specific protumorigenic role for
IL18 was associated with high
IL18 gene expression in the gastric
tumor epithelium compared with IL1β, which was preferentially expressed in immune cells. Supporting an epithelial-specific role for
IL18, we found it to be highly secreted from human
gastric cancer cell lines. Moreover,
IL18 blockade either by a neutralizing anti-IL18 antibody or by CRISPR/Cas9-driven deletion of ASC augmented apoptosis in human
gastric cancer cells. In clinical specimens of human
gastric cancer tumors, we observed a significant positive correlation between elevated mature
IL18 protein and ASC
mRNA levels. Collectively, our findings reveal the ASC/
IL18 signaling axis as a candidate therapeutic target in
gastric cancer.Significance:
Inflammasome activation that elevates
IL18 helps drive
gastric cancer by protecting
cancer cells against apoptosis, with potential implications for new therapeutic strategies in this setting.
Cancer Res; 78(5); 1293-307. ©2017 AACR.