Abstract
SummaryAlthough 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.
Highlights
Blockade of immune checkpoints, including the cytotoxic T lymphocyte-associated protein (CTLA)-4 and the programmed cell death-1 (PD-1)/PD ligand-1 (PD-L1) pathway, have increased overall survival and progression-free survival of cancer patients.only a restricted number of patients show clinical benefits (Syn et al, 2017; Binnewies et al, 2018), suggesting that other immune inhibitory mechanisms may limit the efficacy of these treatments
To determine whether increased neutrophil recruitment upon ATP injection was dependent on inflammasome activation, we generated Tmem176bÀ/ÀCasp1À/À double knockout (DKO) mice (Figure S1A)
Tmem176bÀ/À bone marrow-derived DCs (BMDCs) secreted higher amounts of IL-18 compared with WT cells in a caspase-1-dependent manner (Figure 1H)
Summary
Only a restricted number of patients show clinical benefits (Syn et al, 2017; Binnewies et al, 2018), suggesting that other immune inhibitory mechanisms may limit the efficacy of these treatments. In this regard, high intratumoral K+ leads to T cell dysfunction by inhibiting voltage and Ca2+-dependent K+. We identify the transmembrane protein 176B (TMEM176B) as an innate immune checkpoint that curtails CD8+ T cell-mediated immunity by repressing inflammasome activation. Genetic disruption or pharmacologic inhibition of TMEM176B potentiates antitumor immunity and enhances the efficacy of anti-CTLA-4 and anti-PD-1 antibodies in mice by unleashing inflammasome activation. Targeting TMEM176B may influence antitumor effector mechanisms by de-repressing inflammasome activation
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