CD4⁺ T cells play a crucial role for lenalidomide in vivo anti-tumor activity in murine multiple myeloma.

Lenalidomide modulates the host immune response against myeloma via multiple actions. Although these effects have been elucidated in vitro, the central action of lenalidomide-mediated anti-myeloma immune response in vivo is not clear. To investigate its immune action in vivo, we selected the murine myeloma cell line 5TGM1, which is resistant to direct tumoricidal effects of lenalidomide in vitro and in immunodeficient mice, but sensitive to lenalidomide treatment in 5TGM1-bearing immunocompetent mice. Depletion of CD4+ T cells, but not NK cells, B cells, or CD8+ T cells, deprived lenalidomide of its therapeutic effects on 5TGM1-bearing immunocompetent mice. Lenalidomide significantly increased the numbers of IFN-γ-secreting CD4+ and CD8+ T cells but had no effects on NK cells and B cells in this mouse model. Lenalidomide slightly decreased the number of CD25+Foxp3+ T cells but increased perforin expression in CD8+ T cells in vivo. Using this mouse model for investigation of anti-tumor immune action of lenalidomide, we demonstrated that lenalidomide facilitated a type-1 anti-tumor immune response in vivo. The CD4+ T cell subset may play a critical role in the lenalidomide-mediated anti-myeloma immune response in vivo.