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

• Published in: Cancer discovery Vol. 11; no. 9; pp. 2248 - 2265
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: American Association for Cancer Research 09.04.2021
• Subjects: Immunology; Life Sciences
• ISSN: 2159-8290
• DOI: 10.1158/2159-8290.CD-20-1661

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.