Lenalidomide overcomes the immunosuppression of regulatory CD8+CD28− T-cells

Abstract

Although lenalidomide and pomalidomide are well-established treatment options in patients with multiple myeloma, their immune-modulating effects are not fully understood. While CD8+CD28− regulatory T-cells in patients with hematologic disorders display a known immune-escape mechanism, we show that lenalidomide can overcome the immunosuppressive impact of CD8+CD28− T-cells.We analyzed in vitro the antigen-specific T-cell responses of healthy donors and patients with multiple myeloma with or without the addition of autologous CD8+CD28− T-cells in the absence and presence of lenalidomide. We found that lenalidomide enhances the antigen-specific secretion of IFN-γ and Granzyme B despite the addition of CD8+CD28− T-cells. Furthermore, we showed that lenalidomide inhibits the IL-6 secretion of mononuclear cells, triggered by CD8+CD28− T-cells. The addition of IL-6 counteracts the action of lenalidomide based stimulation of IFN-γ secretion and induction of T-cell maturation but not the secretion of Granzyme B. Surprisingly, pomalidomide failed to induce IL-6 suppression and displayed immunostimulating effects only after a prolonged incubation time. Analysis of the IL-6 modulating cereblon-binding protein KPNA2 showed the similar degradation capacity of lenalidomide and pomalidomide without explaining the divergent effects. In conclusion, we showed that IL-6 and lenalidomide, but not pomalidomide, are opponents in a myeloma-antigen specific T-cell model.

Mass cytometry dissects T cell heterogeneity in the immune tumor microenvironment of common dysproteinemias at diagnosis and after first line therapies

“…The presence of trisomies is a negative prognostic factor in myeloma precursors but a positive one in NDMM, after therapy has been instituted. We have shown that patients with trisomies are especially sensitive to lenalidomide-based therapy 51 and immunomodulation of these inactive subsets by lenalidomide might explain this 4,52 . Senescent/terminally differentiated T cell subsets were also found to be negatively associated with TTP.…”

Mechanisms of failure of chimeric antigen receptor T-cell therapy

“…IKZF1 and IKZF3 are transcription factors that are critical to the differentiation of B cells, lenalidomide can increase serum IL-2 level in vitro by down-regulating the expression of IKZF1/3 [20], thereby promoting the proliferation of natural killer (NK) cells, NK/T cells and CD4 + T cells. In-vitro studies showed that lenalidomide can decrease the amount of IL-6 that was secreted by monocytes and recede the immunosuppression on CART19 cell through the mechanism of reducing the quantity of CD8 + CD28 − Treg cells [21].…”

The Impact of Induction Regimes on Immune Responses in Patients with Multiple Myeloma

“…Second, Rev is involved in disrupting interactions between various components of the BM microenvironment that myeloma cells subvert to promote their survival and proliferation [65]. These include the production of IL-6 by BM stromal cells [66] and mononuclear cells [67], angiogenesis [68], and the complex interplay between myeloma cells, osteoblasts, and osteoclasts [69].…”

“…For example, there are conflicting reports of its effects on Tregs. Most but not all studies indicate that addition of Rev to cell cultures leads to proliferation of T cells with regulatory phenotypes of CD4+CD25+ and CD8+CD28−, in the latter case possibly by the production of IL-10 by DCs [67], although, at least for PBMCs cultured with IL-2, addition of Rev led to a 50% reduction in the number of CTLA-4+CD25 high CD4+ Tregs with decreased FOXP3 expression [31]. Notwithstanding, it is usually found that Rev augments anti-tumor immune activity, as reported by Chung et al, who showed that, at least for post ASCT lenalidomide maintenance therapy, Tregs declined as CD8+ T cells expanded during early lymphocyte recovery [30].…”