Immunomodulatory drugs suppress Th1-inducing ability of dendritic cells but enhance Th2-mediated allergic responses

Abstract

Immunomodulatory drugs (IMiDs), lenalidomide and pomalidomide, are widely used treatments for multiple myeloma; however, they occasionally lead to episodes of itchy skin and rashes. Here, we analyzed the effects of IMiDs on human myeloid dendritic cells (mDCs) as major regulators of Th1 or Th2 responses and the role they play in allergy. We found that lenalidomide and pomalidomide used at clinical concentrations did not affect the survival or CD86 and OX40-ligand expression of blood mDCs in response to lipopolysaccharide (LPS) and thymic stromal lymphopoietin (TSLP) stimulation. Both lenalidomide and pomalidomide dose-dependently inhibited interleukin-12 (IL-12) and TNF production and STAT4 expression, and enhanced IL-10 production in response to LPS. When stimulated with TSLP, both IMiDs significantly enhanced CCL17 production and STAT6 and IRF4 expression and promoted memory Th2-cell responses. In 46 myeloma patients, serum CCL17 levels at the onset of lenalidomide-associated rash were significantly higher than those without rashes during lenalidomide treatment and those before treatment. Furthermore, serum CCL17 levels in patients who achieved a very good partial response (VGPR) were significantly higher compared with a less than VGPR during lenalidomide treatment. The median time to next treatment was significantly longer in lenalidomide-treated patients with rashes than those without. Collectively, IMiDs suppressed the Th1-inducing capacity of DCs, instead promoting a Th2 response. Thus, the lenalidomide-associated rashes might be a result of an allergic response driven by Th2-axis activation. Our findings suggest clinical efficacy and rashes as a side effect of IMiDs are inextricably linked through immunostimulation.

Mechanisms of Immune Evasion in Multiple Myeloma: Open Questions and Therapeutic Opportunities

“…However, and interestingly, an increase in Th2 response has been observed after lenalidomide and pomalidomide treatment. Specifically, patients who developed an IMiDs-related skin rash obtained the best results in the anti-cancer response, raising the attention again on the importance of a Th2 response against MM [56].…”

Preceding bortezomib administration for a certain period reduces the risk of lenalidomide‐induced skin rash

“…8,9 There are also some reports showing cases of eosinophilia with LEN treatment, 15,18,19 which stimulates Th2 memory cells by activation of T cells and dendritic cells (DC) with LEN. 10,[20][21][22] On the other hand, BOR has been shown to exert potent immunomodulatory effects, including the induction of apoptosis of DCs, the decrease in T-cell costimulatory molecules and inflammatory cytokine production, selective apoptosis of activated effector T cells, and inhibition of NF-κB. 13,14 Therefore, it was considered that the development of LEN-induced skin rash could be reduced by the prior administration of BOR.…”

Simple desensitization protocol for multiple myeloma patients with lenalidomide‐induced skin rash: Case series

“…Although the mechanism of LEN-induced skin rash is not clearly understood, it is thought that T cells are importantly involved in its appearance. [14][15][16] It has also been reported that the incidence of LEN-induced skin rash decreases with a history of chemotherapy (especially BOR), 17,18 which has a cell-mediated immunosuppressive effect. Demir et al described a desensitization protocol using corticosteroids, 12 which also has immunosuppressive effects.…”