| Autor: |
Dan Liu, Xuan Zhao, Xiyue Xu, Yulian Dai, Shunshun Bao, Li Zha, Shuci Liu, Yuchen Liu, Junnian Zheng, Ming Shi |
| Jazyk: |
angličtina |
| Rok vydání: |
2021 |
| Předmět: |
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| Zdroj: |
Journal for ImmunoTherapy of Cancer, Vol 9, Iss 1 (2021) |
| Druh dokumentu: |
article |
| ISSN: |
2051-1426 |
| DOI: |
10.1136/jitc-2020-001466 |
| Popis: |
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-1β 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-1β. CAR-T treatment-induced α1-AR-mediated adrenergic signaling augmented the priming of AIM2 inflammasome by enhancing IL-1β 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-1β-related toxic side effects of CAR-T therapy and ensure antitumor effects of the treatment. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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