NLRP3 and cancer: Pathogenesis and therapeutic opportunities

Abstract

More than a decade ago IL-1 blockade was suggested as an add-on therapy for the treatment of cancer. This proposal was based on the overall safety record of anti-IL-1 biologics and the anti-tumor properties of IL-1 blockade in animal models of cancer. Today, a new frontier in IL-1 activity regulation has developed with several orally active NLRP3 inhibitors currently in clinical trials, including cancer. Despite an increasing body of evidence suggesting a role of NLRP3 and IL-1-mediated inflammation driving cancer initiation, immunosuppression, growth, and metastasis, NLRP3 activation in cancer remains controversial. In this review, we discuss the recent advances in the understanding of NLRP3 activation in cancer. Further, we discuss the current opportunities for NLRP3 inhibition in cancer intervention with novel small molecules.

Keywords: Caspase-1; IL-1 family; NLRP3; Pyroptosis; Response to therapy; Tumor microenvironment.

Figure 1.. NLRP3 expression profile in various cancers paired to normal tissues.

Data extrapolated from GEPIA (gene expression profiling interactive analysis) (Tang, et al., 2017).

Figure 2.. Schematic representation of the NLRP3 activation and the subsequent NLRP3 inflammasome formation.

(Left) Engagement of TLRs by PAMPs and DAMPs or cytokine receptors by their respective cytokines (IL-1α, IL-1β, or TNFα) lead to upregulation of NFκB-mediated gene expression of inflammasome components, termed priming. (Right) Activation occurs through PAMPs and DAMPs that activate upstream signals resulting in NLRP3 self-oligomerization (in text). NLRP3 then interacts with ASC, pro-caspase-1 is recruited resulting in caspase-1 activation, activated caspase-1 then cleaves pro-IL-1β and pro-IL-18. Biologically active IL-1β and IL-18 are then secreted into the extracellular space. Abbreviations: interleukin-1 alpha (IL-1α), interleukin-1 beta (IL-1β), interleukin 1 receptor 1 (IL-1R1), tumor necrosis factor α (TNFα), tumor necrosis factor receptor (TNFR), toll-like receptor (TLR), damage-associated molecular patterns (DAMPs), pathogen-associated molecular patterns (PAMPS), ATP (adenosine triphosphate), ADP (adenosine diphosphate), GSDMD (gasdermin D), purinergic receptor P2X7 (P2X7R), nuclear factor-κB (NFκB), reactive oxygen species (ROS), apoptosis-associated speck-like protein containing a CARD (ASC).

Figure 3.. Dual role of NLRP3 in cancer.

Schematization of pro-tumor (left) and anti-tumor (right) functions of NLRP3 in tumor.

Figure 4.. Pyroptotic-mediated fate in phagocytes.

Following recognition of DAMPs or PAMPs, NF-κB translocases in the nuclei of phagocytes like dendritic cells (DCs) mediating the transcription of NLRP3 (inactive) and pro-IL-1β (1.). Next, inflammasome triggers (signal 2) will induce NLRP3 inflammasome formation (2.) Based on the nature of “signal 2”, a different fate for the cell can occur. For example, triggers like oxPLs (top) result in NLRP3 inflammasome formation and hyperactive DCs (3.). Hyperactive DCs remain viable and are able to induce a durable and effective adaptive anti-tumor response while releasing IL-1β and other cytokines like IL-12 and IL-23. On the other hand, triggers like ATP (bottom) result in NLRP3 inflammasome formation and a GSDM-mediated cell death failing in the induction of an effective anti-tumor immunity (3.). Abbreviations: LDH, lactate dehydrogenase enzyme; TLRs, Toll-like receptors; MDSCs, myeloid suppressor cells; HGMB1, High mobility group box 1.

Figure 5.. Mechanisms of NLRP3 activation in tumor.

(Top) Tumor cell-intrinsic mechanisms of NLRP3 activation in the TME. (Bottom) Host cell-intrinsic mechanisms of NLRP3 activation in the TME. Aberrant activation of NLRP3 within the TME results in increased IL-1β and IL-18 secretion. Dysregulation of these cytokines result tumor promoting mechanisms, such as; angiogenesis, immunosuppression and metastasis. NLRP3 activation therefore represents a key immune checkpoint within the TME, acting as a master switch for inflammation-mediated tumor progression.