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

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Targeting TMEM176B Enhances Antitumor Immunity and Augments the Efficacy of Immune Checkpoint Blockers by Unleashing Inflammasome Activation.
Cancer Cell ( IF 48.8 ) Pub Date : 2019-05-13 , DOI: 10.1016/j.ccell.2019.04.003
Mercedes Segovia ₁ , Sofia Russo ₁ , Mathias Jeldres ₂ , Yamil D Mahmoud ₃ , Valentina Perez ₁ , Maite Duhalde ₂ , Pierre Charnet ₄ , Matthieu Rousset ₄ , Sabina Victoria ₂ , Florencia Veigas ₃ , Cédric Louvet ₅ , Bernard Vanhove ₆ , R Andrés Floto ₇ , Ignacio Anegon ₅ , Maria Cristina Cuturi ₅ , M Romina Girotti ₃ , Gabriel A Rabinovich ₈ , Marcelo Hill ₁

Affiliation

Laboratory of Immunoregulation and Inflammation, Institut Pasteur de Montevideo, 11400 Montevideo, Uruguay; Immunobiology Department, Faculty of Medicine, University of the Republic, 11800 Montevideo, Uruguay.
Laboratory of Immunoregulation and Inflammation, Institut Pasteur de Montevideo, 11400 Montevideo, Uruguay.
Laboratories of Immunopathology and Translational Immuno-Oncology, Institute of Biology and Experimental Medicine (IBYME), National Council of Scientific and Technical Investigations (CONICET), C1428 Buenos Aires, Argentina.
Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS ENSCM, Université de Montpellier, 34093 Montpellier, France.
INSERM UMR 1064, Center for Research in Transplantation and Immunology, Université de Nantes, CHU Nantes, Institut de Transplantation Urologie Néphrologie (ITUN), 44093 Nantes, France.
INSERM UMR 1064, Center for Research in Transplantation and Immunology, Université de Nantes, CHU Nantes, Institut de Transplantation Urologie Néphrologie (ITUN), 44093 Nantes, France; Xenothera, 44093 Nantes, France.
Molecular Immunity Unit, Department of Medicine, University of Cambridge, CB2 0QH Cambridge, UK.
Laboratories of Immunopathology and Translational Immuno-Oncology, Institute of Biology and Experimental Medicine (IBYME), National Council of Scientific and Technical Investigations (CONICET), C1428 Buenos Aires, Argentina; Department of Biological Chemistry, School of Exact and Natural Sciences, University of Buenos Aires, C1428 Buenos Aires, Argentina.

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.

中文翻译：

靶向TMEM176B通过释放炎症小体激活来增强抗肿瘤免疫力并增强免疫检查点阻滞剂的功效。

尽管免疫检查点阻断剂已在具有不同恶性肿瘤的患者中产生了显着的临床益处，但这些疗法的疗效仍然有限。在这里，我们表明跨膜蛋白176B（TMEM176B）的破坏通过释放炎性体激活而有助于CD8 + T细胞介导的肿瘤生长抑制。Tmem176b的缺乏通过涉及caspase-1 /IL-1β激活的机制增强了抗CTLA-4抗体的抗肿瘤活性。因此，对检查站封锁疗法有反应的患者表现出激活的炎性体征。最后，我们确定BayK8644为有效的TMEM176B抑制剂，可促进CD8 + T细胞介导的肿瘤控制并增强抗CTLA-4和抗PD-1抗体的抗肿瘤活性。因此，

更新日期：2019-05-16

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