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Lenalidomide potentiates CD4+CD25+Treg-related suppression of lymphoma B-cell proliferation

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Abstract

We have previously found that ex vivo expanded human CD4+CD25+Treg cells suppress proliferation of lymphoma B-cell lines. Here we demonstrate that the immunomodulatory drug lenalidomide potentiates suppression of lymphoma B-cell proliferation by freshly isolated CD4+CD25+Tregs, as well as suppression by Tregs expanded polyclonally in the presence of rapamycin from CD4+CD25+T cells or CD4+CD25+CD127loT cells. The regulation of lymphoma cell proliferation by Tregs pre-expanded with “third-party” allogeneic MoDCs in the presence of rapamycin was also potentiated by lenalidomide. Lenalidomide contributed to the suppression exerted by Tregs despite concomitant downregulation of Treg proliferation. Lenalidomide did not reduce the suppression of conventional T cells by expanded Tregs. The exposure of polyclonally expanded Tregs to lenalidomide did not significantly alter their phenotype. There was no uniform pattern of lenalidomide effect on Treg-mediated regulation of lymphoma B cells freshly isolated from patients. Freshly isolated lymphoma cells activated with multimeric CD40L and IL-4 to support their survival in vitro varied in their sensitivity to lenalidomide, and the regulatory effect of Tregs on such lymphoma cells ranged from suppression to help in individual patients. Lenalidomide potentiated or attenuated Treg effects on the survival of freshly isolated lymphoma cells. A combination of lenalidomide treatment with adoptive transfer of CD4+CD25+Tregs or CD4+CD25+CD127loTregs expanded ex vivo could be used to suppress proliferation of residual lymphoma in select patients with lymphoma responsive to the regulation by Tregs and sensitive to lenalidomide.

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Acknowledgments

Contribution: M.A.G. designed and performed experiments, analyzed data, made the figures, and cowrote the manuscript; I.S.B. and E.N. performed experiments, analyzed data, and made the figures; G.R. and E.P.-K. provided patient samples, analyzed data, and cowrote the manuscript; K.B. analyzed patient samples; M. Biernacka designed and performed experiments; M. Bujko performed experiments, analyzed data, and cowrote the manuscript, J.W. designed and supervised the study, and cowrote the manuscript; S.M designed and supervised the study, analyzed data, and cowrote the manuscript. This work was supported by a grant from National Science Centre, Poland (N N402 454739), for S.M.

Funding

This work was supported by a grant from National Science Centre, Poland (N N402 454739), for S.M.

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Authors and Affiliations

  1. Department of Immunology, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, 5 WK Roentgen Str., 02-781, Warsaw, Poland

    Monika Anna Grygorowicz, Ilona Sara Borycka, Eliza Nowak, Marzena Biernacka & Sergiusz Markowicz

  2. Department of Lymphoid Malignancies, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland

    Ewa Paszkiewicz-Kozik & Jan Walewski

  3. Department of Pathology and Laboratory Diagnostics, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland

    Grzegorz Rymkiewicz & Katarzyna Błachnio

  4. Department of Molecular and Translational Oncology, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland

    Mateusz Bujko

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  1. Monika Anna Grygorowicz
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  2. Ilona Sara Borycka
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  7. Marzena Biernacka
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  10. Sergiusz Markowicz
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Correspondence to Sergiusz Markowicz.

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Conflict of interest

JW.: Roche, Takeda, Mundipharma, Celgene, Teva, Gilead, Sanofi—lecture honoraria, Roche, Takeda, Janssen-Cilag, Teva, Boehringer Ingelheim, Celgene, Mundipharma, Karyopharm, Ariad—consulting/advisory role, Roche, Mundipharma, Celgene, GSK/Novartis—research funding, Roche, Celgene, Takeda, Seattle Genetics, Sanofi—travel/accommodation expenses; E.P.-K: Roche—lecture honoraria, advisory role, travel/accommodation expenses, Sandoz—lecture honoraria; M.A.G., M.Biernacka, M.Bujko, E.N., G.R., I.S.B., Z.B. and S.M. declared no conflict of interest.

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Grygorowicz, M.A., Borycka, I.S., Nowak, E. et al. Lenalidomide potentiates CD4+CD25+Treg-related suppression of lymphoma B-cell proliferation. Clin Exp Med 17, 193–207 (2017). https://doi.org/10.1007/s10238-016-0411-8

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