TMEM176B Is a Potential Inflammasome-Associated Immune Checkpoint

Targeted immune checkpoint therapeutics such as anti-CTLA4 and anti–PD-1 antibodies have significantly increased the survival of cancer patients but are not widely effective; recently, immunogenic chemotherapy followed by activation of the NLRP3 inflammasome has been shown to sensitize tumors to immune checkpoint blockade. Segovia, Russo, and colleagues investigated the role of transmembrane protein 176B (TMEM176B), an immunoregulatory, nonselective cation channel, on inflammasome regulation. Tmem176b^−/− mice exhibited increased NLRP3 inflammasome activation upon treatment with ATP, a known NLRP3 inflammasome activator. Bone marrow–derived dendritic cells (BMDC) from Tmem176b^−/− mice exhibited increased secretion of IL1β and IL18, which are products of activated inflammasomes, and increased cytosolic Ca²⁺ levels; inhibition of Ca²⁺-dependent K⁺ channels resulted in decreased IL1β secretion and inflammasome activation in wild-type (WT) BMDCs. Compared to WT mice, Tmem176b^−/− mice harboring solid tumors had increased overall survival and decreased tumor growth accompanied by increased classic DC caspase-1 activity and higher numbers of TCRβ⁺ CD4⁺ RORγt⁺ cells in tumor-draining lymph nodes (TDLN) and total intratumoral CD8⁺ T cells. Inflammasome-related genes, including TMEM176B, were upregulated in patients responding to anti–PD-1 therapies. A drug library screen identified the Ca²⁺ channel inhibitor BayK8644as a potential modulator of TMEM176B-mediated ion flux. Treatment of WT BMDCs with BayK8644 phenocopied TMEM176B KO BMDCs, inducing IL1β secretion and caspase-1 activity. In vivo, BayK8644 increased survival of tumor-bearing mice and increased CD8⁺ T-cell antitumor toxicity. Cotreatment with an anti-CTLA4 or anti–PD-1 antibody significantly improved survival of tumor-bearing mice and increased the frequency of TCRβ⁺ CD4⁺ RORγt⁺ cells in TDLNs and CD8⁺ T cells in the tumor microenvironment. Together, these results describe the role of TMEM176B in inflammasome regulation and antitumor immunity and suggest that targeting TMEM176B to activate the inflammasome may be a viable therapeutic strategy to improve the efficacy of immune checkpoint blockers.

Segovia M, Russo S, Jeldres M, Mahmoud YD, Perez V, Duhalde M, et al. Targeting TMEM176B enhances antitumor immunity and augments the efficacy of immune checkpoint blockers by unleashing inflammasome activation. Cancer Cell 2019;35:767–81.

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