IFNγ is critical for CAR T cell–mediated myeloid activation and induction of endogenous immunity

Darya Alizadeh, Robyn A. Wong, Sharareh Gholamin, Madeleine Maker, Maryam Aftabizadeh, Xin Yang, Joseph R. Pecoraro, John D. Jeppson, Dongrui Wang, Brenda Aguilar, Renate Starr, Claire B. Larmonier, Nicolas Larmonier, Min Hsuan Chen, Xiwei Wu, Antoni Ribas, Behnam Badie, Stephen J. Forman, Christine E. Brown

Research output: Contribution to journalArticlepeer-review

50 Scopus citations


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. IFNγ production by CAR T cells and IFNγ 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 IL13Rα2–CAR T cells activate patient-derived endogenous T cells and monocytes/macrophages through IFNγ 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 IFNγ 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.

Original languageEnglish (US)
Pages (from-to)2248-2265
Number of pages18
JournalCancer discovery
Issue number9
StatePublished - Sep 2021

ASJC Scopus subject areas

  • Oncology


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