Severe COVID-19 is associated with hyperinflammation and weak T cell responses against SARS-CoV-2. However, the links between those processes remain partially characterized. Moreover, whether and how therapeutically manipulating T cells may benefit patients are unknown. Our genetic and pharmacological evidence demonstrates that the ion channel TMEM176B inhibited inflammasome activation triggered by SARS-CoV-2 and SARS-CoV-2-related murine ß-coronavirus. Tmem176b-/- mice infected with murine ß-coronavirus developed inflammasome-dependent T cell dysfunction and critical disease, which was controlled by modulating dysfunctional T cells with PD-1 blockers. In critical COVID-19, inflammasome activation correlated with dysfunctional T cells and low monocytic TMEM176B expression, whereas PD-L1 blockade rescued T cell functionality. Here, we mechanistically link T cell dysfunction and inflammation, supporting a cancer immunotherapy to reinforce T cell immunity in critical ß-coronavirus disease.
Resumen: La mucositis es un efecto adverso frecuente e invalidante en los pacientes oncológicos que reciben tratamiento de Radioterapia y Quimioterapia a altas dosis y muchas veces lleva a la suspensión del tratamiento. Si bien es una entidad que tiene gran relevancia en los pacientes e importante impacto económico en las instituciones de salud, no existen tratamientos claramente establecidos ni eficaces para mejorar esta condición. El objetivo de esta revisión es analizar la evidencia disponible en el tratamiento de la mucositis, y el respaldo científico e impacto que tienen conductas habitualmente tomadas en su tratamiento.
Abstract: Mucositis is a frequent and disabling adverse effect in cancer patients who received radiation therapy and chemotherapy at high doses and often discontinues treatment. Although it is an entity that has great relevance in patients and an important economic impact in health institutions, there are no clearly established or modified treatments to improve this condition. The objective of this review is to analyze the available evidence in the treatment of mucositis, and the scientific support and impact of behaviors commonly taken in its treatment.
Resumo: A mucosite é um efeito adverso frequente e incapacitante em pacientes com câncer que receberam radioterapia e quimioterapia em altas doses e muitas vezes interrompe o tratamento. Embora seja uma entidade que tenha grande relevância nos pacientes e um importante impacto econômico nas instituições de saúde, não existem tratamentos claramente estabelecidos ou modificados para melhorar essa condição. O objetivo desta revisão é analisar as evidências disponíveis no tratamento da mucosite, o suporte científico e o impacto das condutas comumente adotadas no seu tratamento.
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-1ß 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.
Antineoplastic Agents/pharmacology , Inflammasomes/drug effects , Inflammasomes/immunology , Membrane Proteins/metabolism , Neoplasms/drug therapy , Neoplasms/immunology , 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester/pharmacology , Animals , Antibodies, Monoclonal/pharmacology , CD8-Positive T-Lymphocytes/drug effects , CHO Cells , Cell Line , Cell Line, Tumor , Cell Proliferation/drug effects , Cricetulus , Female , Humans , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Neoplasms/metabolism , Xenopus laevis/metabolism
