Frontiers in Immunology (Mar 2020)
Tumor-Derived Extracellular Vesicles Impair CD171-Specific CD4+ CAR T Cell Efficacy
- Solin Ali,
- Karin Toews,
- Silke Schwiebert,
- Anika Klaus,
- Annika Winkler,
- Laura Grunewald,
- Lena Oevermann,
- Lena Oevermann,
- Hedwig E. Deubzer,
- Hedwig E. Deubzer,
- Hedwig E. Deubzer,
- Hedwig E. Deubzer,
- Alicia Tüns,
- Michael C. Jensen,
- Michael C. Jensen,
- Michael C. Jensen,
- Anton G. Henssen,
- Anton G. Henssen,
- Angelika Eggert,
- Angelika Eggert,
- Angelika Eggert,
- Angelika Eggert,
- Johannes H. Schulte,
- Johannes H. Schulte,
- Johannes H. Schulte,
- Esther Schwich,
- Vera Rebmann,
- Alexander Schramm,
- Annette Künkele,
- Annette Künkele,
- Annette Künkele,
- Annette Künkele
Affiliations
- Solin Ali
- Department of Pediatric Oncology and Hematology, Berlin Institute of Health, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt—Universität zu Berlin, Berlin, Germany
- Karin Toews
- Department of Pediatric Oncology and Hematology, Berlin Institute of Health, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt—Universität zu Berlin, Berlin, Germany
- Silke Schwiebert
- Department of Pediatric Oncology and Hematology, Berlin Institute of Health, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt—Universität zu Berlin, Berlin, Germany
- Anika Klaus
- Department of Pediatric Oncology and Hematology, Berlin Institute of Health, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt—Universität zu Berlin, Berlin, Germany
- Annika Winkler
- Department of Pediatric Oncology and Hematology, Berlin Institute of Health, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt—Universität zu Berlin, Berlin, Germany
- Laura Grunewald
- Department of Pediatric Oncology and Hematology, Berlin Institute of Health, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt—Universität zu Berlin, Berlin, Germany
- Lena Oevermann
- Department of Pediatric Oncology and Hematology, Berlin Institute of Health, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt—Universität zu Berlin, Berlin, Germany
- Lena Oevermann
- Berlin Institute of Health (BIH), Berlin, Germany
- Hedwig E. Deubzer
- Department of Pediatric Oncology and Hematology, Berlin Institute of Health, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt—Universität zu Berlin, Berlin, Germany
- Hedwig E. Deubzer
- Neuroblastoma Research Group, Experimental and Clinical Research Center (ECRC) of the Charité and the Max-Delbrück-Center for Molecular Medicine (MDC) in the Helmholtz Association, Berlin, Germany
- Hedwig E. Deubzer
- German Cancer Consortium (DKTK), Heidelberg, Germany
- Hedwig E. Deubzer
- German Cancer Research Center (DKFZ), Heidelberg, Germany
- Alicia Tüns
- Department of Internal Medicine, University Duisburg-Essen, Essen, Germany
- Michael C. Jensen
- Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA, United States
- Michael C. Jensen
- Fred Hutchinson Cancer Research Center, Seattle, WA, United States
- Michael C. Jensen
- University of Washington, Department of Bioengineering, Seattle, WA, United States
- Anton G. Henssen
- Department of Pediatric Oncology and Hematology, Berlin Institute of Health, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt—Universität zu Berlin, Berlin, Germany
- Anton G. Henssen
- Berlin Institute of Health (BIH), Berlin, Germany
- Angelika Eggert
- Department of Pediatric Oncology and Hematology, Berlin Institute of Health, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt—Universität zu Berlin, Berlin, Germany
- Angelika Eggert
- Berlin Institute of Health (BIH), Berlin, Germany
- Angelika Eggert
- German Cancer Consortium (DKTK), Heidelberg, Germany
- Angelika Eggert
- German Cancer Research Center (DKFZ), Heidelberg, Germany
- Johannes H. Schulte
- Department of Pediatric Oncology and Hematology, Berlin Institute of Health, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt—Universität zu Berlin, Berlin, Germany
- Johannes H. Schulte
- German Cancer Consortium (DKTK), Heidelberg, Germany
- Johannes H. Schulte
- German Cancer Research Center (DKFZ), Heidelberg, Germany
- Esther Schwich
- 0Department of Transfusion Medicine, University Duisburg-Essen, Essen, Germany
- Vera Rebmann
- 0Department of Transfusion Medicine, University Duisburg-Essen, Essen, Germany
- Alexander Schramm
- Department of Internal Medicine, University Duisburg-Essen, Essen, Germany
- Annette Künkele
- Department of Pediatric Oncology and Hematology, Berlin Institute of Health, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt—Universität zu Berlin, Berlin, Germany
- Annette Künkele
- Berlin Institute of Health (BIH), Berlin, Germany
- Annette Künkele
- German Cancer Consortium (DKTK), Heidelberg, Germany
- Annette Künkele
- German Cancer Research Center (DKFZ), Heidelberg, Germany
- DOI
- https://doi.org/10.3389/fimmu.2020.00531
- Journal volume & issue
-
Vol. 11
Abstract
Chimeric antigen receptor (CAR) T cell efficacy against solid tumors is currently limited by several immune escape mechanisms, which may include tumor-derived extracellular vesicles. Advanced neuroblastoma is an aggressive childhood tumor without curative treatment options for most relapsed patients today. We here evaluated the role of tumor-derived extracellular vesicles on the efficacy of CAR T cells targeting the neuroblastoma-specific antigen, CD171. For this purpose, CAR T cell activation, cytokine production, exhaustion, and tumor cell-directed cytotoxicity upon co-culture was evaluated. Tumor-derived extracellular vesicles isolated from SH-SY5Y neuroblastoma cells neither affected CAR T cell activation nor expression of inhibitory markers. Importantly, exposure of CD4+ CD171-specific CAR T cells to tumor-derived extracellular vesicles significantly impaired tumor cytotoxicity of CAR T cells. This effect was independent of neurotrophic receptor tyrosine kinases 1 or 2 (NTRK1, NTRK2) expression, which is known to impact immune responses against neuroblastoma. Our results demonstrate for the first time the impact of tumor-derived extracellular vesicles and non-cell-mediated tumor-suppressive effects on CD4+ CAR T cell efficacy in a preclinical setting. We conclude that these factors should be considered for any CAR T cell-based therapy to make CAR T cell therapy successful against solid tumors.
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