Helmholtz Gemeinschaft


Tumor-derived extracellular vesicles impair CD171-specific CD4(+) CAR T cell efficacy

PDF (Original Article) - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
[img] Other (Supplementary Material)

Item Type:Article
Title:Tumor-derived extracellular vesicles impair CD171-specific CD4(+) CAR T cell efficacy
Creators Name:Ali, S. and Toews, K. and Schwiebert, S. and Klaus, A. and Winkler, A. and Grunewald, L. and Oevermann, L. and Deubzer, H.E. and Tüns, A. and Jensen, M.C. and Henssen, A.G. and Eggert, A. and Schulte, J.H. and Schwich, E. and Rebmann, V. and 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
Publisher:Frontiers Media SA
Page Range:531
Date:31 March 2020
Official Publication:https://doi.org/10.3389/fimmu.2020.00531
PubMed:View item in PubMed

Repository Staff Only: item control page


Downloads per month over past year

Open Access
MDC Library