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

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. NevalaEsteban Braggio, Wei Ding, Sameer A. Parikh, Neil E. Kay, Saad S. Kenderian

Research output: Contribution to journal › Article › peer-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 language	English (US)
Pages (from-to)	1529-1540
Number of pages	12
Journal	Molecular Therapy
Volume	29
Issue number	4
DOIs	https://doi.org/10.1016/j.ymthe.2020.12.033
State	Published - Apr 7 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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10.1016/j.ymthe.2020.12.033

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Cox, M. J., Lucien, F., Sakemura, R., Boysen, J. C., Kim, Y., Horvei, P., Manriquez Roman, C., Hansen, M. J., Tapper, E. E., Siegler, E. L., Forsman, C., Crotts, S. B., Schick, K. J., Hefazi, M., Ruff, M. W., Can, I., Adada, M., Bezerra, E., Kankeu Fonkoua, L. A., ... Kenderian, S. S. (2021). Leukemic extracellular vesicles induce chimeric antigen receptor T cell dysfunction in chronic lymphocytic leukemia. Molecular Therapy, 29(4), 1529-1540. https://doi.org/10.1016/j.ymthe.2020.12.033

Cox, MJ, Lucien, F , Sakemura, R, Boysen, JC, Kim, Y, Horvei, P, Manriquez Roman, C, Hansen, MJ, Tapper, EE, Siegler, EL, Forsman, C, Crotts, SB, Schick, KJ, Hefazi, M, Ruff, MW, Can, I, Adada, M, Bezerra, E, Kankeu Fonkoua, LA, Nevala, WK, Braggio, E, Ding, W, Parikh, SA , Kay, NE & Kenderian, SS 2021, 'Leukemic extracellular vesicles induce chimeric antigen receptor T cell dysfunction in chronic lymphocytic leukemia', Molecular Therapy, vol. 29, no. 4, pp. 1529-1540. https://doi.org/10.1016/j.ymthe.2020.12.033

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title = "Leukemic extracellular vesicles induce chimeric antigen receptor T cell dysfunction in chronic lymphocytic leukemia",

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",

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

note = "Publisher Copyright: {\textcopyright} 2020 The American Society of Gene and Cell Therapy",

year = "2021",

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doi = "10.1016/j.ymthe.2020.12.033",

language = "English (US)",

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AU - Cox, Michelle J.

AU - Lucien, Fabrice

AU - Sakemura, Reona

AU - Boysen, Justin C.

AU - Kim, Yohan

AU - Horvei, Paulina

AU - Manriquez Roman, Claudia

AU - Hansen, Michael J.

AU - Tapper, Erin E.

AU - Siegler, Elizabeth L.

AU - Forsman, Cynthia

AU - Crotts, Sydney B.

AU - Schick, Kendall J.

AU - Hefazi, Mehrdad

AU - Ruff, Michael W.

AU - Can, Ismail

AU - Adada, Mohamad

AU - Bezerra, Evandro

AU - Kankeu Fonkoua, Lionel Aurelien

AU - Nevala, Wendy K.

AU - Braggio, Esteban

AU - Ding, Wei

AU - Parikh, Sameer A.

AU - Kay, Neil E.

AU - Kenderian, Saad S.

PY - 2021/4/7

Y1 - 2021/4/7

N2 - 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.

AB - 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.

KW - CART cell exhaustion

KW - chimeric antigen receptor T cells

KW - chronic lymphocytic leukemia

KW - extracellular vesicles

KW - microenvironment

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

Abstract

Keywords

ASJC Scopus subject areas

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