Tumor-Derived Extracellular Vesicles Impair CD171-Specific CD4 + CAR T Cell Efficacy

• Published in: Frontiers in immunology 2020-03, Vol.11, p.531-531
• Main Authors: Ali, Solin, Toews, Karin, Schwiebert, Silke, Klaus, Anika, Winkler, Annika, Grunewald, Laura, Oevermann, Lena, Deubzer, Hedwig E, Tüns, Alicia, Jensen, Michael C, Henssen, Anton G, Eggert, Angelika, Schulte, Johannes H, Schwich, Esther, Rebmann, Vera, Schramm, Alexander, Künkele, Annette
• Format: Article
• Language: English
• Subjects: Antigens, Neoplasm - immunology; CD4-Positive T-Lymphocytes - immunology; Cell Line, Tumor; Extracellular Vesicles - immunology; Extracellular Vesicles - metabolism; Humans; Immunology; immunotherapy; Immunotherapy, Adoptive; neuroblastoma; Neuroblastoma - immunology; neurotrophic receptor tyrosine kinase; pediatric oncology; Receptors, Chimeric Antigen - immunology; solid tumors
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2020.00531

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.