Inflammasome Adaptor ASC Suppresses Apoptosis of Gastric Cancer Cells by an IL18-Mediated Inflammation-Independent Mechanism

Abstract

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 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. 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. .

Diverging inflammasome signals in tumorigenesis and potential targeting

“…2a) Notably, IL-18 but not IL-1β, produced from gastric epithelium promotes the development of gastric tumor in gp130 F/F mice [G] as a downstream effect of inflammasome activation. IL-18 inhibits caspase 8-mediated apoptosis in gastric cancer cells thereby promoting cell survival in a cell-autonomous manner 32 . Furthermore, IL-18 production from immune cells in the particular study is not sufficient to drive gastric tumorigenesis, suggesting that IL-18 production from epithelial tumor cells rather than immune cells is detrimental.…”

“…Although IL-1β does not have such a role in survival, it also accelerates gastric tumorigenesis by a different mechanism, discussed in detail in the immunosuppressive section 33 . Therefore, the functional dichotomy between IL-18 and IL-1β in gastric cancer could be explained, at least in part, by IL-18 acting on epithelial (tumor) cells expressing higher levels of IL-18R to promote cell survival 32 , whereas IL-1β-responsive immune cells provide a tumor-supporting microenvironment 33 . However, IL-1R signaling is important for proliferation of tumor cells in a spontaneous model of breast cancer 34 .…”

Dual Role of Inflammasome Adaptor ASC in Cancer

“…A pro-tumorigenic function for ASC, through its effector cytokine IL-18, was recently described in gastric cancer (Deswaerte et al, 2018), where ASC was significantly upregulated in the tumor compared to normal gastric tissue. Mechanistic studies were performed on spontaneous mouse models of gastric cancer.…”

NLRP3 Inflammasome From Bench to Bedside: New Perspectives for Triple Negative Breast Cancer

“…Low CASP-1 expression is correlated with tumor stage, metastasis and patient survival (47). Another study revealed increased expression of ASC and IL-18 in GC, suggesting a pro-tumorigenic effect for ASC by preserving cells against apoptosis (48). These findings indicate that GC may result from the activation of different pathways dependent on the NLRP3 inflammasome and make the latter a potential therapeutic target, although further investigations are required to confirm such a possibility (49).…”