Abstract
Simple SummaryThe tumor-intrinsic NLRP3 inflammasome is a newly recognized player in the regulation of tumor-directed immune responses and promises to provide fresh insight into how tumors respond to immunotherapy. This brief review discusses recent data describing how activation of the tumor-intrinsic NLRP3 inflammasome contributes to immune evasion and what this pathway may provide to the field of immuno-oncology both in terms of pharmacologic targets capable of boosting responses to checkpoint inhibitor therapies and predictive biomarkers indicating which tumors may be most susceptible to these new therapeutic strategies.The tumor-intrinsic NOD-like receptor family, pyrin-domain-containing-3 (NLRP3) inflammasome, plays an important role in regulating immunosuppressive myeloid cell populations in the tumor microenvironment (TME). While prior studies have described the activation of this inflammasome in driving pro-tumorigenic mechanisms, emerging data is now revealing the tumor NLRP3 inflammasome and the downstream release of heat shock protein-70 (HSP70) to regulate anti-tumor immunity and contribute to the development of adaptive resistance to anti-PD-1 immunotherapy. Genetic alterations that influence the activity of the NLRP3 signaling axis are likely to impact T cell-mediated tumor cell killing and may indicate which tumors rely on this pathway for immune escape. These studies suggest that the NLRP3 inflammasome and its secreted product, HSP70, represent promising pharmacologic targets for manipulating innate immune cell populations in the TME while enhancing responses to anti-PD-1 immunotherapy. Additional studies are needed to better understand tumor-specific regulatory mechanisms of NLRP3 to enable the development of tumor-selective pharmacologic strategies capable of augmenting responses to checkpoint inhibitor immunotherapy while minimizing unwanted off-target effects. The execution of upcoming clinical trials investigating this strategy to overcome anti-PD-1 resistance promises to provide novel insight into the role of this pathway in immuno-oncology.
Highlights
Much of our understanding of anti-tumor immunity is based on studies focused on the adaptive immune response to cancer
Studies have implicated the NLRP3-mediated release of IL-1β in the induction of the IL-22 cytokine by CD4+ T cells, a process observed to support tumor cell proliferation and growth [48]. These data are consistent with the findings reported in the CANTOS clinical trial, which was originally designed to examine the impact of the IL-1β antagonistic antibody, canakinumab, on recurrent vascular events in patients with a prior myocardial infarction and persistently elevated C-reactive protein
CXCR2-dependent chemokines in primary melanoma tissues [54] (Figure 1). We verified that these changes correlated with an increased flux of PMN-myeloid-derived suppressor cells (MDSCs) into tumors, a process that was reversed by tumor-directed genetic silencing of CXCL5 as well as small molecule inhibition of CXCR2
Summary
Much of our understanding of anti-tumor immunity is based on studies focused on the adaptive immune response to cancer. Several gain-of-function mutations in the NLRP3 gene, as well as its regulators, have been identified and associated with various clinical inflammatory syndromes [1,8] It is this association between NLRP3 and these inflammatory conditions, which has prompted the development of various pharmacologic inhibitors to suppress the activity of the NLRP3 inflammasome and manage the symptoms of these rare disorders [9,10]. After briefly discussing prior studies implicating a role for the NLRP3 inflammasome in both cancer progression and the regulation of the adaptive immune system, this review focuses on developments that indicate an important role for the tumor-intrinsic NLRP3 inflammasome in acquired immunotherapy resistance via the induction of heat shock protein-70. Additional discussion is provided regarding the influence that the genetics of this inflammasome pathway may have on immunotherapy resistance and in the identification of those tumors more likely to be responsive to the pharmacologic inhibition of the tumor NLRP3-HSP70 signaling axis
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