title: Lenalidomide induces immunomodulation in chronic lymphocytic leukemia and enhances antitumor immune responses mediated by NK and CD4 T cells.
abstract: Lenalidomide is an immunomodulatory drug with therapeutic activity in chronic lymphocytic leukemia (CLL). However, it has pleiotropic effects, and the mechanism of action responsible for its therapeutic activity has not been well defined yet. Herein, we show that lenalidomide treatment does not have an effect on the proliferation of leukemia cells, but it increases the proliferation of B cells from healthy donors. Lenalidomide did not exert a direct effect on the apoptosis of leukemia cells obtained from CLL patients, although it indirectly induced their apoptosis through the activation of nonmalignant immune cells. Thus, lenalidomide markedly increased the proliferation of NK and CD4 T cells. The effect of lenalidomide on NK cells was secondary to the induction of IL-2 production by CD4 T cells. Accordingly, depletion of T cells or blockade of IL-2 activity completely abrogated the proliferation of NK cells. Additionally, lenalidomide enhanced NK and NKT-like cell-mediated natural cytotoxicity against leukemia cells from CLL patients. Lenalidomide also upregulated CD20 expression on leukemia cells and, accordingly, it had a synergistic effect with rituximab on promoting antibody-dependent cell-mediated cytotoxicity against primary leukemia cells. Overall, these observations provide a support for combining lenalidomide with rituximab as a treatment in CLL.
authors.affiliation: Department of Functional Biology, IUOPA, University of Oviedo, Facultad de Medicina, Julian Claveria sn, 33006 Oviedo, Spain.
authors.forename: Andrea
authors.initials: A
authors.lastname: Acebes-Huerta
authors.affiliation: Department of Functional Biology, IUOPA, University of Oviedo, Facultad de Medicina, Julian Claveria sn, 33006 Oviedo, Spain.
authors.forename: Leticia
authors.initials: L
authors.lastname: Huergo-Zapico
authors.affiliation: Department of Hematology, Hospital Universitario Central de Asturias, C/Celestino Villamil s/n, 33006 Oviedo, Spain.
authors.forename: Ana Pilar
authors.initials: AP
authors.lastname: Gonzalez-Rodriguez
authors.affiliation: Department of Functional Biology, IUOPA, University of Oviedo, Facultad de Medicina, Julian Claveria sn, 33006 Oviedo, Spain.
authors.forename: Azahara
authors.initials: A
authors.lastname: Fernandez-Guizan
authors.affiliation: Department of Hematology, Hospital Universitario Central de Asturias, C/Celestino Villamil s/n, 33006 Oviedo, Spain.
authors.forename: Angel R
authors.initials: AR
authors.lastname: Payer
authors.affiliation: Department of Functional Biology, IUOPA, University of Oviedo, Facultad de Medicina, Julian Claveria sn, 33006 Oviedo, Spain.
authors.forename: Alejandro
authors.identifier: 0000-0002-6360-5205
authors.initials: A
authors.lastname: López-Soto
authors.affiliation: Department of Functional Biology, IUOPA, University of Oviedo, Facultad de Medicina, Julian Claveria sn, 33006 Oviedo, Spain.
authors.forename: Segundo
authors.initials: S
authors.lastname: Gonzalez
mesh_terms: D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D056747:Immunomodulation / Q000187:drug effects*; D007376:Interleukin-2 / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D000077269:Lenalidomide; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D016131:Lymphocyte Subsets / Q000187:drug effects; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D007376:Interleukin-2; D013792:Thalidomide; D000077269:Lenalidomide