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

Abstract

BackgroundInterleukin (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.MethodsThe 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.ResultsThis 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.ConclusionOur 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.

Mechanisms of cytokine release syndrome and neurotoxicity of CAR T-cell therapy and associated prevention and management strategies

“…Pyroptotic macrophages consequently produce more DAMPs and proinflammatory factors, creating a vicious cycle and leading to the further activation of macrophages [22]. Additionally, the dsDNA-mediated absent in melanoma 2 (AIM2) inflammasome pathway could be involved in caspase 1 formation [24]. Macrophages phagocytize dsDNA released by pyroptotic tumor cells and activate the AIM2 inflammasome, which is a dsDNA sensor, in the cytoplasm.…”

“…Macrophages phagocytize dsDNA released by pyroptotic tumor cells and activate the AIM2 inflammasome, which is a dsDNA sensor, in the cytoplasm. Similar to the NLRP3 inflammasome pathway, activated AIM2 forms an AIM2/ ASC-pro-caspase 1 complex to trigger caspase 1-dependent IL-1β maturation [24], thereby causing more IL-1β release and aggravation of CRS.…”

“…drainage of serous effusion, airway protection, regulation of intestinal flora) [43] •Supportive management •EEG, neuroimaging •Tocilizumab (only when concurrent with CRS), corticosteroids, anti-epileptics drugs •ICU treatment, airway protection, specific neurointensive treatment [224] and hemodynamic instability, which are common clinical features of CRS [27]. In addition, catecholamines are produced after the coculture of CAR T-cells and malignant cells, which may be involved in cytokine release [24,28]. By binding α1-adrenergic receptors (ARs) on the surface of macrophages, catecholamines can enhance the AIM2/ ASC-caspase-1 pathway and further promote IL-1β production and macrophage pyroptosis [22,24].…”

“…In addition, catecholamines are produced after the coculture of CAR T-cells and malignant cells, which may be involved in cytokine release [24,28]. By binding α1-adrenergic receptors (ARs) on the surface of macrophages, catecholamines can enhance the AIM2/ ASC-caspase-1 pathway and further promote IL-1β production and macrophage pyroptosis [22,24]. In addition, catecholamines lead to a self-amplifying feed-forward loop in macrophages, promoting the release of catecholamines, IL-6 and other cytokines, including macrophage inflammatory protein (MIP)-1α, IFN-γ, IL-2 and TNF [28].…”

CAR-T Plus Radiotherapy: A Promising Combination for Immunosuppressive Tumors

“…Similarly, TAM can be co-opted by tumor cells and polarized to an anti-inflammatory M2-like phenotype capable of hindering T cell responses by the production of inhibitory mediators (i.e., TGF-β, indoleamine 2,3-dioxygenase IDO) and expression of PD-L1 ( 54 , 55 ). Direct depletion of TAM has proven ineffective in promoting ACT, however, re-wiring of TAM to a pro-inflammatory phenotype by anti-CD40 agonist or blocking AIM2 inflammasome can improve the performance of immunotherapies including CAR-T cells ( 56 , 57 ).…”