Multimodality Targeting of Dendritic Cell Vaccination Combined with Immunomodulatory Drug and Immune Checkpoint Blockade Has Synergistically Induced a Marked Tumor Regression By Modulating Tumor Microenvironment in a Murine Myeloma Model

There is emerging evidence that the maximal benefit of dendritic cell (DC)-based cancer immunotherapy may be achieved by combination with other therapies that act to immunomodulation and tumor microenvironment. In this study, we tried to obtain the best efficacy of immunotherapy using DC vaccination in combination with lenalidomide and PD-1 blockade in a murine myeloma model. After establishing myeloma-bearing mice, five treatment groups were designed to be a mimic protocol as like treatment in clinics as following: 1) PBS control, 2) DCs, 3) DCs + lenalidomide, 4) DCs + PD-1 blockade, and 5) DCs + lenalidomide + PD-1 blockade. After treatment, preclinical response and in vitro immunological responses were evaluated. DCs combined with lenalidomide and PD-1 blockade showed the best tumor regression among the study groups. These anti-tumor effects have meaningfully related to the decrease of immuno-regulatory populations, such as myeloid-derived suppressor cells (MDSCs), M2 macrophages, and regulatory T cells (Treg) and the increase of effector immune cell populations, including CD4⁺ and CD8⁺ T cells, natural killer (NK) cells, and M1 macrophages, accompanied with the activation of cytotoxic T lymphocytes (CTLs) and NK cells in the splenocytes from the treated mice. Moreover, the level of immunosuppressive cytokines, such as TGF-ß and IL-10, was significantly reduced in tumor microenvironment. DC vaccination in combination with lenalidomide plus PD-1 blockade has synergistically induced a strong antitumor immunity by modulating tumor microenvironment in a murine myeloma model. This protocol will become a promising translational approach to improve the efficacy of immunotherapy in the field of MM.