Molecular Action of Lenalidomide in Lymphocytes and Hematologic Malignancies

Figure 1

Various T-cell signaling pathways are upregulated after lenalidomide treatment. Lenalidomide is known to have no direct mitogenic activity, therefore it cannot induce proliferation directly. Upon TCR ligation, lenalidomide (LEN) increases phosphorylation of tyrosines within the intracytoplasmic tail of CD28, through an unknown mechanism, increasing downstream signaling and activation of PKC-θ, MAPK, and potentially other signaling pathways. These pathways lead to the activation of classic T-cell transcription factors like AP-1, NFAT-1, and NF-κB that induce secretion of the T helper type 1 (Th-1) cytokines interleukin-2 (IL-2), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ). Though it is controversial which transcription factors are ultimately increased upon lenalidomide treatment (indicated by a question mark). Upregulation of these pathways potentially reverses T-cell defects, aids in breaking tolerance, and leads to greater CD4+ T-cell help to DCs, NK cells, and CD8+ T cells, augmenting eradication of the tumor cells.