Expansion of polyfunctional antigen-specific T-cells upon stimulation with mRNA electroporated dendritic cells in the presence of immunomodulatory drugs

Since its FDA approval, thalidomide/dexamethasone combination therapy has been successfully used in first-line multiple myeloma treatment. More active and less toxic thalidomide-derivatives such as lenalidomide and pomalidomide have been developed. Thalidomide and its derivatives exert direct anti-tumor effects but are also strong stimulators of NK-cell and polyclonal T-cell responses and are therefore referred to as immunomodulatory drugs (IMiDs). We hypothesize that the immunostimulatory properties of IMiDs could improve the efficacy of immunotherapies, such as dendritic cell-based vaccines. In this study, we therefore aim to investigate the effects of IMiDs on antigen-specific T-cell responses in vitro.
Since it has been demonstrated that disease progression during HIV infection is not merely determined by the number of HIV-specific T cells, but rather by their quality, strategies to specifically enhance or induce high quality HIV-specific T-cell responses are necessary to develop effective HIV immune therapies. Therefore, we decided to evaluate the effects of lenalidomide and pomalidomide on HIV-specific T cells. We found that the presence of IMiDs during in vitro T-cell stimulation with dendritic cells electroporated with Gag or Nef encoding mRNA resulted in an increased HIV-specific CD8+ T-cell proliferation and cytokine (IFN-g, TNF-a and IL-2) production. Interestingly, the IMiDs particularly enhanced polyfunctional HIV-specific CD8+ T cells, which were previously shown to be associated with a better HIV disease control. Furthermore, CD8+ T cells responded to lower antigenic peptide concentrations and recognized a higher number of Gag epitopes upon addition of IMiDs. As opposed to the CD8+ T-cell proliferation, IMiDs reduced the proliferation of the HIV-specific CD4+ T cells while increasing the number of polyfunctional CD4+ T cells, be it to a lesser extent compared to the CD8+ T cells.
These results provide new information about the effects of IMiDs on antigen-specific T cells and suggest that these drugs might increase the efficacy of immune therapies for infectious diseases and cancer.