Targeting TMEM176B Enhances Antitumor Immunity and Augments the Efficacy of Immune Checkpoint Blockers by Unleashing Inflammasome Activation

Cancer Cell. 2019 May 13;35(5):767-781.e6. doi: 10.1016/j.ccell.2019.04.003.


Although immune checkpoint blockers have yielded significant clinical benefits in patients with different malignancies, the efficacy of these therapies is still limited. Here, we show that disruption of transmembrane protein 176B (TMEM176B) contributes to CD8+ T cell-mediated tumor growth inhibition by unleashing inflammasome activation. Lack of Tmem176b enhances the antitumor activity of anti-CTLA-4 antibodies through mechanisms involving caspase-1/IL-1β activation. Accordingly, patients responding to checkpoint blockade therapies display an activated inflammasome signature. Finally, we identify BayK8644 as a potent TMEM176B inhibitor that promotes CD8+ T cell-mediated tumor control and reinforces the antitumor activity of both anti-CTLA-4 and anti-PD-1 antibodies. Thus, pharmacologic de-repression of the inflammasome by targeting TMEM176B may enhance the therapeutic efficacy of immune checkpoint blockers.

Keywords: TMEM176B; cancer; dendritic cells; immune checkpoint blockers; inflammasome; ion channel.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / pharmacology
  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Antineoplastic Agents / pharmacology*
  • CD8-Positive T-Lymphocytes / drug effects
  • CHO Cells
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cricetulus
  • Female
  • Humans
  • Inflammasomes / drug effects*
  • Inflammasomes / immunology*
  • Male
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Neoplasms / drug therapy*
  • Neoplasms / immunology*
  • Neoplasms / metabolism
  • Xenopus laevis / metabolism


  • Antibodies, Monoclonal
  • Antineoplastic Agents
  • Inflammasomes
  • Membrane Proteins
  • Tmem176B protein, mouse
  • 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester