Abstract
Lenalidomide is an analog of thalidomide, with potent anticancer activity demonstrated in several hematological malignancies. It has immunomodulatory properties, being able to enhance the activation of different types of immune cells, which results in antitumor activities. Dendritic cells (DCs) are pivotal in the immune response, and different immunotherapeutic approaches targeting these cells are being developed. Since little is known about the effect of lenalidomide on DCs, the goal of the present work was to investigate the phenotype and function of human monocyte-derived DCs differentiated in the presence of lenalidomide (L-DCs). Our results showed that L-DCs display a unique phenotype, with increased cell surface expression of some maturation markers such as CD1d, CD83, CD86, and HLA-DR. This phenotype correlates with a lower expression of the E3 ubiquitin-ligase MARCH-I in L-DCs, upregulating the cell surface expression of CD86 and HLA-DR. In addition, immature L-DCs express higher amounts of DC-SIGN on the cell surface than control immature DCs. After LPS stimulation, production of IL-6 and TNF-α was severely decreased, whereas IL-12 and IL-10 secretion was dramatically upregulated in L-DCs, compared to that in the controls. Functionally, L-DCs are more effectively recognized by NKT cells in cytotoxicity experiments. Furthermore, L-DCs display higher opsonin-independent antigen uptake capability than control DCs. Mixed lymphocyte reaction experiments showed that L-DCs could stimulate naïve CD4 T-cells, polarizing them toward a predominant Th1 phenotype. In summary, DCs derived from monocytes in the presence of lenalidomide present a semi-mature phenotype, increased phagocytic capacity, reduced production of proinflammatory cytokines, and the ability to polarize T-cells toward predominant Th1-type responses; these are qualities that might be useful in the development of new immunotherapeutic treatments.
Highlights
Lenalidomide (Revlimid®) is a derivative of thalidomide (Thalomid®) [1] approved for the treatment of multiple myeloma (MM), myelodysplastic syndromes associated with 5q cytogenetic abnormalities, and mantle cell lymphoma [2]
The data presented in this paper indicate that Dendritic cells (DCs) differentiated from monocytes in the presence of lenalidomide (L-DCs) have a phenotype that could be considered as semi-mature, when compared with control immature dendritic cells (iDCs)
The higher expression of CD1d appears to be controlled at a transcriptional level, since in L-DCs, there is an upregulation of the CD1D-encoding mRNA, which is paired to the downregulation of CD1A mRNA
Summary
Lenalidomide (Revlimid®) is a derivative of thalidomide (Thalomid®) [1] approved for the treatment of multiple myeloma (MM), myelodysplastic syndromes associated with 5q cytogenetic abnormalities, and mantle cell lymphoma [2]. Lenalidomide exerts direct tumoricidal activity as well as stimulating antitumor immune responses [3]. It can mediate some of its antitumoral and immunomodulatory activities through the action of the cullin-RINGE3 ubiquitin ligase complex CRL4CRBN [4], promoting the degradation of certain substrates, such as the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) [4], as well as the casein kinase 1A1 (CK1a) [5]. Lenalidomide is able to inhibit proliferation [6] and induce the apoptosis of cancer cells [7, 8] It interferes with the stromal support of tumor cells by blocking the production of cytokines and growth factors necessary for the cancer cells’ survival [9]. NKT cells, which are specialized T lymphocytes that recognize glycolipidic antigens presented by CD1d molecules, are activated by lenalidomide, which enhances the response of these cells against tumors [20]
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