ALIZADEH, D.; WONG, R.A.; GHOLAMIN, S.; MAKER, M.; AFTABIZADEH, M.; YANG, X.; PECORARO, J.R.; JEPPSON, J.D.; WANG, D.; AGUILAR, B.; STARR, R.; LARMONIER, C.B.; LARMONIER, Nicolas; CHEN, M.-H.; WU, X.; RIBAS, A.; BADIE, B.; FORMAN, S.J.; BROWN, C.E.

doi:10.1158/2159-8290.CD-20-1661

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Cancer Discovery. 2021-04-09, vol. 11, n° 9, p. 2248-2265

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Chimeric antigen receptor (CAR) T cells mediate potent antigen-specific antitumor activity; however, their indirect effects on the endogenous immune system are not well characterized. Remarkably, we demonstrate that CAR T-cell treatment of mouse syngeneic glioblastoma (GBM) activates intratumoral myeloid cells and induces endogenous T-cell memory responses coupled with feed-forward propagation of CAR T-cell responses. IFN? production by CAR T cells and IFN? responsiveness of host immune cells are critical for tumor immune landscape remodeling to promote a more activated and less suppressive tumor microenvironment. The clinical relevance of these observations is supported by studies showing that human IL13R?2-CAR T cells activate patient-derived endogenous T cells and monocytes/macrophages through IFN? signaling and induce the generation of tumor-specific T-cell responses in a responding patient with GBM. These studies establish that CAR T-cell therapy has the potential to shape the tumor microenvironment, creating a context permis-sible for eliciting endogenous antitumor immunity. Significance: Our findings highlight the critical role of IFN? signaling for a productive CAR T-cell therapy in GBM. We establish that CAR T cells can activate resident myeloid populations and promote endogenous T-cell immunity, emphasizing the importance of host innate and adaptive immunity for CAR T-cell therapy of solid tumors.< Réduire

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IFN? is critical for CAR T cell-mediated myeloid activation and induction of endogenous immunity

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