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Research Watch

TMEM176B Is a Potential Inflammasome-Associated Immune Checkpoint

DOI: 10.1158/2159-8290.CD-RW2019-077 Published July 2019
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  • Major finding: TMEM176B inhibits activation of NLRP3 inflammasome, linking adaptive and innate antitumor responses.

  • Mechanism: TMEM176B-mediated inhibition of cytosolic Ca2+ accumulation ablates inflammasome-derived caspase-1/IL1β.

  • Impact: Inflammasome activation may enhance the efficacy of immune checkpoint therapies.


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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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Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.

  • ©2019 American Association for Cancer Research.
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Cancer Discovery: 9 (7)
July 2019
Volume 9, Issue 7
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TMEM176B Is a Potential Inflammasome-Associated Immune Checkpoint
Cancer Discov July 1 2019 (9) (7) OF9; DOI: 10.1158/2159-8290.CD-RW2019-077

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TMEM176B Is a Potential Inflammasome-Associated Immune Checkpoint
Cancer Discov July 1 2019 (9) (7) OF9; DOI: 10.1158/2159-8290.CD-RW2019-077
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