Blockade of AIM2 inflammasome or α1-AR ameliorates IL-1ß release and macrophage-mediated immunosuppression induced by CAR-T treatment.
J Immunother Cancer
; 9(1)2021 01.
Article
en En
| MEDLINE
| ID: mdl-33414262
ABSTRACT
BACKGROUND:
Interleukin (IL) 1 released from monocytes/macrophages is one of the critical determinants in mediating the adverse events of chimeric antigen receptor T cell (CAR-T) therapy, including cytokine release syndrome and neurotoxicity. However, the molecular mechanisms of IL-1 production during CAR-T therapy remain unknown.METHODS:
The roles of AIM2 and α1-adrenergic receptor (α1-AR) in CAR-T treatment-induced IL-1ß release were evaluated by gene silencing, agonist or antagonist treatment. The phenotype switch of macrophages in response to CAR-T treatment was analyzed concerning cytotoxicity of CAR-T cells and proliferation of activated T cells.RESULTS:
This study provided the experimental evidence that CAR-T treatment-induced activation of AIM2 inflammasome of macrophages resulted in the release of bioactive IL-1ß. CAR-T treatment-induced α1-AR-mediated adrenergic signaling augmented the priming of AIM2 inflammasome by enhancing IL-1ß mRNA and AIM2 expression. Meanwhile, tumor cell DNA release triggered by CAR-T treatment potentiated the activation of AIM2 inflammasome in macrophages. Interestingly, an apparent phenotypic switch in macrophages occurred after interacting with CAR-T/tumor cells, which greatly inhibited the cytotoxicity of CAR-T cells and proliferation of activated T cells through upregulation of programmed cell death-ligand 1 (PD-L1) and indoleamine 2,3-dioxygenase (IDO) in the macrophages. Blockade of AIM2 inflammasome or α1-AR reversed the upregulation of PD-L1 and IDO and the phenotypic switch of the macrophages.CONCLUSION:
Our study implicates that CAR-T therapy combined with the blockade of AIM2 inflammasome or α1-AR may relieve IL-1ß-related toxic side effects of CAR-T therapy and ensure antitumor effects of the treatment.Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Inmunoterapia Adoptiva
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Receptores Adrenérgicos alfa
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Proteínas de Unión al ADN
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Interleucina-1beta
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Receptores Quiméricos de Antígenos
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Macrófagos
/
Neoplasias
Límite:
Humans
Idioma:
En
Revista:
J Immunother Cancer
Año:
2021
Tipo del documento:
Article
País de afiliación:
China