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Publications

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Ppublish 125 citations

PubMed: 33837065 DOI: 10.1158/2159-8290.CD-20-1661

IFNγ Is Critical for CAR T Cell-Mediated Myeloid Activation and Induction of Endogenous Immunity.

Cancer Discov 11(9):2248-2265

Authors: 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

Affiliations

  • T Cell Therapeutics Research Labs, Cellular Immunotherapy Center, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California.
  • T Cell Therapeutics Research Labs, Cellular Immunotherapy Center, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California.
  • Department of Biology and Bioengineering, California Institute of Technology, Pasadena, California.
  • Department of Biopathology, Molecular Pathology Unit, Bergonié Institute, Comprehensive Cancer Center, Bordeaux, France.
  • CNRS UMR 5164, ImmunoConcEpT, University of Bordeaux, Bordeaux, France.
  • Core of Integrative Genomics, City of Hope Comprehensive Cancer Center, Duarte, California.
  • Department of Medicine, Jonsson Comprehensive Cancer Center at University of California, Los Angeles, California.
  • Division of Neurosurgery, Department of Surgery, City of Hope, Duarte, California.

Abstract

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 permissible 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..

MeSH

Cells, Neoplasms, Immunity, Therapeutics, T-Lymphocytes, Tumor Microenvironment, Car-T Cell

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