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

Michelle J Cox; Fabrice Lucien; 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 Nevala; Esteban Braggio; Wei Ding; Sameer A Parikh; Neil E Kay; Saad S Kenderian

doi:10.1016/j.ymthe.2020.12.033

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

Mol Ther. 2021 Apr 7;29(4):1529-1540. doi: 10.1016/j.ymthe.2020.12.033. Epub 2021 Jan 1.

Authors

Michelle J Cox¹, Fabrice Lucien², Reona Sakemura³, Justin C Boysen⁴, Yohan Kim², Paulina Horvei⁵, Claudia Manriquez Roman⁶, Michael J Hansen⁷, Erin E Tapper³, Elizabeth L Siegler³, Cynthia Forsman⁸, Sydney B Crotts⁹, Kendall J Schick¹⁰, Mehrdad Hefazi³, Michael W Ruff¹¹, Ismail Can¹², Mohamad Adada¹³, Evandro Bezerra¹³, Lionel Aurelien Kankeu Fonkoua¹³, Wendy K Nevala⁷, Esteban Braggio¹⁴, Wei Ding⁴, Sameer A Parikh⁴, Neil E Kay¹⁵, Saad S Kenderian¹⁶

Affiliations

¹ T Cell Engineering, Mayo Clinic, Rochester, MN, USA; Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA; University of Minnesota Graduate School, Bioinformatics and Computational Biology, Minneapolis, MN, USA.
² Department of Urology, Mayo Clinic, Rochester, MN, USA.
³ T Cell Engineering, Mayo Clinic, Rochester, MN, USA; Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA.
⁴ Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA.
⁵ T Cell Engineering, Mayo Clinic, Rochester, MN, USA; Department of Pediatric Hematology/Oncology, Mayo Clinic, Rochester, MN, USA.
⁶ T Cell Engineering, Mayo Clinic, Rochester, MN, USA; Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA; Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN, USA; Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.
⁷ Department of Immunology, Mayo Clinic, Rochester, MN, USA.
⁸ T Cell Engineering, Mayo Clinic, Rochester, MN, USA.
⁹ Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN, USA; Department of Immunology, Mayo Clinic, Rochester, MN, USA.
¹⁰ T Cell Engineering, Mayo Clinic, Rochester, MN, USA; Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA; Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN, USA; Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.
¹¹ T Cell Engineering, Mayo Clinic, Rochester, MN, USA; Department of Neurology, Mayo Clinic, Rochester, MN, USA.
¹² T Cell Engineering, Mayo Clinic, Rochester, MN, USA; Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA; Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN, USA; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA.
¹³ T Cell Engineering, Mayo Clinic, Rochester, MN, USA; Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA; Department of Oncology, Mayo Clinic, Rochester, MN, USA.
¹⁴ Department of Cancer Biology, Mayo Clinic, Phoenix, AZ, USA.
¹⁵ Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA; Department of Immunology, Mayo Clinic, Rochester, MN, USA.
¹⁶ T Cell Engineering, Mayo Clinic, Rochester, MN, USA; Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA; Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN, USA; Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA; Department of Immunology, Mayo Clinic, Rochester, MN, USA. Electronic address: [email protected].

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.

Keywords: CART cell exhaustion; chimeric antigen receptor T cells; chronic lymphocytic leukemia; extracellular vesicles; microenvironment.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

B7-H1 Antigen / blood*
B7-H1 Antigen / genetics
Cell Line, Tumor
Extracellular Vesicles / genetics
Extracellular Vesicles / immunology
Female
Humans
Immunotherapy, Adoptive / methods
Leukemia, Lymphocytic, Chronic, B-Cell / blood
Leukemia, Lymphocytic, Chronic, B-Cell / genetics
Leukemia, Lymphocytic, Chronic, B-Cell / pathology
Leukemia, Lymphocytic, Chronic, B-Cell / therapy*
Male
Receptors, Antigen, T-Cell / blood
Receptors, Antigen, T-Cell / genetics*
Receptors, Antigen, T-Cell / immunology
Receptors, Chimeric Antigen / genetics*
Receptors, Chimeric Antigen / immunology
T-Lymphocytes / immunology
Tumor Microenvironment / drug effects

Substances

B7-H1 Antigen
Receptors, Antigen, T-Cell
Receptors, Chimeric Antigen

Abstract

Publication types

MeSH terms

Substances

Grants and funding