The emerging roles of inflammasome‐dependent cytokines in cancer development

Abstract

In addition to the genomic alterations that occur in malignant cells, the immune system is increasingly appreciated as a critical axis that regulates the rise of neoplasms and the development of primary tumours and metastases. The interaction between inflammatory cell infiltrates and stromal cells in the tumour microenvironment is complex, with inflammation playing both pro‐ and anti‐tumorigenic roles. Inflammasomes are intracellular multi‐protein complexes that act as key signalling hubs of the innate immune system. They respond to cellular stress and trauma by promoting activation of caspase‐1, a protease that induces a pro‐inflammatory cell death mode termed pyroptosis along with the maturation and secretion of the pro‐inflammatory cytokines interleukin (IL)‐1β and IL‐18. Here, we will briefly introduce inflammasome biology with a focus on the dual roles of inflammasome‐produced cytokines in cancer development. Despite emerging insight that inflammasomes may promote and suppress cancer development according to the tumour stage and the tumour microenvironment, much remains to be uncovered. Further exploration of inflammasome biology in tumorigenesis should enable the development of novel immunotherapies for cancer patients.

Therapeutic modulation of inflammasome pathways

“…Therapeutic targeting of IL-1 family cytokines, and IL-1β in particular, has gained significant traction due to its central role in a host of autoinflammatory diseases. 90,91 Moreover, results from both clinical trials and preclinical studies implicate IL-1β in a suite of metabolic, malignant, and neurodegenerative diseases. [90][91][92] IL-1β is a highly inflammatory and pyrogenic cytokine, and its production and activity are tightly regulated.…”

“…90,91 Moreover, results from both clinical trials and preclinical studies implicate IL-1β in a suite of metabolic, malignant, and neurodegenerative diseases. [90][91][92] IL-1β is a highly inflammatory and pyrogenic cytokine, and its production and activity are tightly regulated. Cells of the myeloid lineage-the primary source of IL-1β in the body-do not express IL-1β in the absence of inflammatory cues, and first need to transcriptionally upregulate its production in the context of infection or tissue damage.…”

“…A vast body of studies has implicated the NLRP3 inflammasome in a host of inflammatory, metabolic, and neurodegenerative diseases, rendering this pathway an attractive target for pharmacological modulation across therapeutic areas. 60,91,92,114 The first demonstration that selective pharmacological inhibition of the NLRP3 inflammasome is feasible arrived in 2009 with the demonstration that the sulfonylurea-containing compound glyburide inhibited NLRP3induced pyroptosis and IL-1β secretion without affecting activation of the NLRC4 and NLRP1b inflammasomes. 115 The half-inhibitory concentration (IC 50 ) of glyburide is in the low μM range, whereas the related diarylsulfonylurea compound MCC950/CRID3 inhibits NLRP3 activation with nM potency.…”

Dual Role of Inflammasome Adaptor ASC in Cancer

“…The role of inflammasomes in cancer has been recently discussed elsewhere (Kolb et al, 2014;Kantono and Guo, 2017;Karan, 2018;Karki and Kanneganti, 2019;Van Gorp and Lamkanfi, 2019). We refer readers interested in comprehensive summaries of the field to those reviews.…”

Inflammasome- and gasdermin D-independent IL-1β production mobilizes neutrophils to inhibit antitumor immunity

“…Interleukin-1β (IL-1β) is a pro-inflammatory cytokine whose role in cancer is increasingly recognized [4][5][6]. In a recent study, long-term treatment with a neutralizing anti-IL-1β antibody led to a dose-dependent reduction of lung cancer incidence and mortality in a large cohort of atherosclerosis patients with a history of myocardial infarction [7].…”