| First Author | Alizadeh D | Year | 2021 |
| Journal | Cancer Discov | Volume | 11 |
| Issue | 9 | Pages | 2248-2265 |
| PubMed ID | 33837065 | Mgi Jnum | J:337160 |
| Mgi Id | MGI:6757905 | Doi | 10.1158/2159-8290.CD-20-1661 |
| Citation | Alizadeh D, et al. (2021) IFNgamma is Critical for CAR T Cell-mediated Myeloid Activation and Induction of Endogenous Immunity. Cancer Discov |
| abstractText | 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. IFNgamma production by CAR T cells and IFNgamma 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 IL13Ralpha2-CAR T cells activate patient-derived endogenous T cells and monocytes/macrophages through IFNgamma 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 permissible for eliciting endogenous antitumor immunity. SIGNIFICANCE: Our findings highlight the critical role of IFNgamma 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. |
