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| Item Type: | Article |
|---|---|
| Title: | Tumor-derived extracellular vesicles impair CD171-specific CD4(+) CAR T cell efficacy |
| Creators Name: | Ali, S., Toews, K., Schwiebert, S., Klaus, A., Winkler, A., Grunewald, L., Oevermann, L., Deubzer, H.E., Tüns, A., Jensen, M.C., Henssen, A.G., Eggert, A., Schulte, J.H., Schwich, E., Rebmann, V., Schramm, A. and Künkele, A. |
| 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. |
| Keywords: | Immunotherapy, Pediatric Oncology, Neuroblastoma, Solid Tumors, Neurotrophic Receptor Tyrosine Kinase |
| Source: | Frontiers in Immunology |
| ISSN: | 1664-3224 |
| Publisher: | Frontiers Media SA |
| Volume: | 11 |
| Page Range: | 531 |
| Date: | 31 March 2020 |
| Official Publication: | https://doi.org/10.3389/fimmu.2020.00531 |
| PubMed: | View item in PubMed |
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