Lenalidomide Synergistically Enhances the Effect of Dendritic Cell Vaccination in a Model of Murine Multiple Myeloma

Abstract

We investigated the efficacy of lenalidomide (LEN) in combination with dendritic cell (DC) vaccination in the MOPC-315 murine myeloma model. After tumor growth, LEN was injected intraperitoneally for 4 consecutive days in combination with DC vaccination. The combination of LEN and vaccination efficiently inhibited tumor growth compared with the single agents alone. A cytotoxic assay revealed that the anticancer effects of DC vaccination plus LEN involved not only generation of antigen-specific cytotoxic T lymphocytes but also NK cells. Vaccinated mice had reduced numbers of suppressor cells, including both myeloid-derived suppressor cells and regulatory T cells, in the spleen. The proportions of CD4+ and CD8+ T cells increased in the spleen, and a Th1 cytokine (interferon-γ) rather than a Th2 cytokine (interleukin-10) was synthesized in response to tumor antigens. LEN enhanced the innate immune response by modulating NK cell numbers and function. In addition, LEN reduced the production levels of angiogenesis-inducing factors in tumor-bearing mice. Together, these results suggest that a combination of LEN and DC vaccination may synergistically enhance anticancer immunity in the murine myeloma model, by inhibiting immunosuppressor cells and stimulating effector cells, as well as effectively polarizing the Th1/Th2 balance in favor of a Th1-specific immune response.

APRIL and BCMA promote human multiple myeloma growth and immunosuppression in the bone marrow microenvironment

“…These critical immune suppressive checkpoint molecules are significantly elevated in patient MM cells vs normal PCs and further support MM cell growth and survival, as well as inhibit various effector cellmediated anti-MM immune responses. [63][64][65][66][67][68][69][70][71][72] For example, PD-L1 is induced in MM cells by interferon g, IL-6, and stromal cells. [64][65][66]73 It increases tumor growth and mediates tumor-induced immune inhibition.…”

Combination therapy with dendritic cells and lenalidomide is an effective approach to enhance antitumor immunity in a mouse colon cancer model

“…Additionally, the down-regulation of B cell counts by lenalidomide may be linked to its activity in B cell malignancies. In our previous study, lenalidomide synergistically enhanced the anticancer immunity of DC vaccination in a murine multiple myeloma (MM) model by inhibiting immunosuppressor cells, stimulating effector T and NK cells and inducing strong Th1-type immunity [29]. …”

“…Thus, we considered that the use of lenalidomide may enhance the tumor microenvironment and danger signals for generating potent Th1-type immune responses and antitumor immunity. Recently, several DC-based vaccines using known tumor antigens in mouse colon cancer models have been documented [16, 17, 29–32]. In our study, dying tumor cells were used to load DCs to generate tumor-specific CTLs in tumor-bearing mice.…”

Activation of NK cells and disruption of PD-L1/PD-1 axis: two different ways for lenalidomide to block myeloma progression

“…Interestingly, it has been reported that DC play a dual opposite role as promoter of CD8+ T cells-mediated MM cell killing and as facilitator of MM cell resistance to CD8(+) T-cell killing [36]. Additionally, a positive effect in DC activation mediated by Lenalidomide treatment has been observed in both MM patients [37] and murine MM model [38]. Macrophages represent an important population in the MM microenvironment [39].…”