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

Authors

  • S. Ali
  • K. Toews
  • S. Schwiebert
  • A. Klaus
  • A. Winkler
  • L. Grunewald
  • L. Oevermann
  • H.E. Deubzer
  • A. Tüns
  • M.C. Jensen
  • A.G. Henssen
  • A. Eggert
  • J.H. Schulte
  • E. Schwich
  • V. Rebmann
  • A. Schramm
  • A. Künkele

Journal

  • Frontiers in Immunology

Citation

  • Front Immunol 11: 531

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.


DOI

doi:10.3389/fimmu.2020.00531