Leukemic extracellular vesicles induce chimeric antigen receptor T cell dysfunction in chronic lymphocytic leukemia

Michelle J. Cox, Lucien-Matteoni Fabrice, Reona Sakemura, Justin C. Boysen, Yohan Kim, Paulina Horvei, Claudia Manriquez Roman, Michael J. Hansen, Erin E. Tapper, Elizabeth L. Siegler, Cynthia Forsman, Sydney B. Crotts, Kendall J. Schick, Mehrdad Hefazi, Michael W. Ruff, Ismail Can, Mohamad Adada, Evandro Bezerra, Lionel Aurelien Kankeu Fonkoua, Wendy K. NevalaEsteban D Braggio, Wei Ding, Sameer A. Parikh, Neil Elliot Kay, Saad Kenderian

Research output: Contribution to journalArticlepeer-review

Abstract

Chimeric antigen receptor (CAR) T cell therapy has yielded unprecedented outcomes in some patients with hematological malignancies; however, inhibition by the tumor microenvironment has prevented the broader success of CART cell therapy. We used chronic lymphocytic leukemia (CLL) as a model to investigate the interactions between the tumor microenvironment and CART cells. CLL is characterized by an immunosuppressive microenvironment, an abundance of systemic extracellular vesicles (EVs), and a relatively lower durable response rate to CART cell therapy. In this study, we characterized plasma EVs from untreated CLL patients and identified their leukemic cell origin. CLL-derived EVs were able to induce a state of CART cell dysfunction characterized by phenotypical, functional, and transcriptional changes of exhaustion. We demonstrate that, specifically, PD-L1+ CLL-derived EVs induce CART cell exhaustion. In conclusion, we identify an important mechanism of CART cell exhaustion induced by EVs from CLL patients.

Original languageEnglish (US)
JournalMolecular Therapy
DOIs
StateAccepted/In press - 2021

Keywords

  • CART cell exhaustion
  • chimeric antigen receptor T cells
  • chronic lymphocytic leukemia
  • extracellular vesicles
  • microenvironment

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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