Blockade of AIM2 inflammasome or α1-AR ameliorates IL-1β release and macrophage-mediated immunosuppression induced by CAR-T treatment

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 alpha 1-adrenergic receptor (alpha 1-AR) in CAR-T treatment-induced IL-1 beta 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-1 beta. CAR-T treatment-induced alpha 1-AR-mediated adrenergic signaling augmented the priming of AIM2 inflammasome by enhancing IL-1 beta 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 alpha 1-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 alpha 1-AR may relieve IL-1 beta-related toxic side effects of CAR-T therapy and ensure antitumor effects of the treatment.

Automated summary

This study demonstrates that CAR-T therapy induces activation of the AIM2 inflammasome in macrophages, leading to the release of bioactive IL-1 beta. Additionally, the alpha 1-AR-mediated adrenergic signaling enhances the priming of AIM2 inflammasome, while tumor cell DNA release triggers inflammasome activation. The interaction between CAR-T cells and tumor cells causes a phenotypic switch in macrophages, inhibiting the cytotoxicity of CAR-T cells and T cell proliferation through upregulation of PD-L1 and IDO.