Enhanced radiation-induced immunogenic cell death activates chimeric antigen receptor T cells by targeting CD39 against glioblastoma

Abstract

Chimeric antigen receptor (CAR)-T cells directed to solid tumors have been less effective, due in part to the low or lost expression of specific tumor antigens. Herein, we developed a different strategy to enhance CAR-T cell persistence and efficacy by producing a multispecific CAR-T or vaccine based on immunogenic cell death (ICD). We demonstrated that ionizing radiation activates STAT1-IRF1-CD39 axis to upregulate CD39 expression to form an immunosuppressive tumor microenvironment (TME) to enhance radioresistance. CD39 blockade accumulates extracellular ATP, which activates NLRP3 inflammasome in dendritic cells via P2X7 receptor, thereby promoting radiation-induced ICD. Multispecific CAR-T cells in vitro prepared by elevated ICD suppress the growth of xenografts in nude mice. Radiation and CD39 inhibition-induced ICD of glioma stem cells as a vaccine enhance CAR-T expansion in peripheral blood, multifunctionality in the TME, and antitumor effect in a glioma model. The multispecificity of CAR-T cells, targeting CAR and tumor antigens, vastly enhances the function of conventional CAR-T cells, stimulates a native immune response, and overcomes obstacles of specific antigen loss or low expression of target cells in antitumor therapy.

CAR-T cell therapy in multiple myeloma: Current limitations and potential strategies

“…On the one hand, radiotherapy and cryoablation could directly destroy tumor cells; On the other hand, they could sensitize CAR-T cells and activate endogenous effector T cells through the abscopal effect, which may be associated with the upregulation of intratumoral chemokines and cytokines and the release of neo-antigens ( 119 – 121 ). In particular, radiotherapy could also activate CAR-T cells through immunogenic cell death ( 122 ).…”

Amplifying “eat me signal” by immunogenic cell death for potentiating cancer immunotherapy

“…84 against tumor cells. 36 The multiple specificity of CAR-T cells targeting CAR and tumor antigens improves the functions of traditional CAR-T cells and antitumor immunity as well as surmounts the limitations of specific antigen lost or lowly expressed in target cells (Figure 5).…”

“…35 Both are necessary for the optimal activation of tumorspecific immune responses. 36 In the settings, DC precursors newly recruited into the tumor microenvironment through ATP released by tumor cells succumbing to ICD mature during ATP-triggered inflammasome activation and migrate to tumor-draining lymph nodes or tertiary lymphoid structure to initiate adaptive antitumor immunity as well as recruit IL17-producing γδ T-cell population that is required for initiating tumor infiltration by primed CTLs. 37…”

“…Extracellular ATP exerts two primary functions: (i) as a chemotactic cue for myeloid cells, it binds to the purinergic receptor P2Y2 (P2RY2), a metabotropic receptor; (ii) it facilitates the activation of inflammasome to bind to the ionotropic receptor P2RX7 and thus contributes to CASP1‐dependent secretion of interleukin‐1β (IL‐1β) and IL‐18 35 . Both are necessary for the optimal activation of tumor‐specific immune responses 36 . In the settings, DC precursors newly recruited into the tumor microenvironment through ATP released by tumor cells succumbing to ICD mature during ATP‐triggered inflammasome activation and migrate to tumor‐draining lymph nodes or tertiary lymphoid structure to initiate adaptive antitumor immunity as well as recruit IL17‐producing γδ T‐cell population that is required for initiating tumor infiltration by primed CTLs 37 …”

Prodrug-loaded semiconducting polymer hydrogels for deep-tissue sono-immunotherapy of orthotopic glioblastoma

“…25 Traditional therapies including radiotherapy and chemotherapy could improve the immunogenicity of tumors via inducing immunogenic cell death (ICD) of dying tumor cells. [26][27][28][29] Therefore, a combination of ICD induction with immunotherapy is a promising strategy to treat GBM. For example, local delivery of an ICD inducer doxorubicin and a Toll-like receptor (TLR)-9 agonist CpG into tumors elicited antitumor CD8 + T cell responses and reduced the infiltration of M2-like tumor-associated macrophages and myeloid-derived suppressor cells in the brain TME.…”