title: Lenalidomide potentiates CD4+CD25+Treg-related suppression of lymphoma B-cell proliferation.
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.
authors.affiliation: Department of Immunology, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, 5 WK Roentgen Str., 02-781, Warsaw, Poland.
authors.forename: Monika Anna
authors.initials: MA
authors.lastname: Grygorowicz
authors.affiliation: Department of Immunology, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, 5 WK Roentgen Str., 02-781, Warsaw, Poland.
authors.forename: Ilona Sara
authors.initials: IS
authors.lastname: Borycka
authors.affiliation: Department of Immunology, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, 5 WK Roentgen Str., 02-781, Warsaw, Poland.
authors.forename: Eliza
authors.initials: E
authors.lastname: Nowak
authors.affiliation: Department of Lymphoid Malignancies, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Paszkiewicz-Kozik
authors.affiliation: Department of Pathology and Laboratory Diagnostics, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Rymkiewicz
authors.affiliation: Department of Pathology and Laboratory Diagnostics, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Błachnio
authors.affiliation: Department of Immunology, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, 5 WK Roentgen Str., 02-781, Warsaw, Poland.
authors.forename: Marzena
authors.initials: M
authors.lastname: Biernacka
authors.affiliation: Department of Molecular and Translational Oncology, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland.
authors.forename: Mateusz
authors.initials: M
authors.lastname: Bujko
authors.affiliation: Department of Lymphoid Malignancies, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland.
authors.forename: Jan
authors.initials: J
authors.lastname: Walewski
authors.affiliation: Department of Immunology, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, 5 WK Roentgen Str., 02-781, Warsaw, Poland. sergiusz@coi.waw.pl.
authors.forename: Sergiusz
authors.identifier: http://orcid.org/0000-0003-1280-6514
authors.initials: S
authors.lastname: Markowicz
mesh_terms: D000328:Adult; D000368:Aged; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology* / Q000502:physiology; D001782:Blood Donors; D015704:CD4 Antigens / Q000032:analysis; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000378:metabolism*; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D000077269:Lenalidomide; D008223:Lymphoma / Q000276:immunology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020123:Sirolimus / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000737:chemistry / Q000276:immunology*; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D015704:CD4 Antigens; C508017:IL2RA protein, human; D007155:Immunologic Factors; D053645:Interleukin-2 Receptor alpha Subunit; D013792:Thalidomide; D000077269:Lenalidomide; D020123:Sirolimus
keywords: B-cell lymphoma; Lenalidomide; Regulatory T cells