Lenalidomide Enhances Antigen-Specific Activity and Decreases CD45RA Expression of T Cells from Patients with Multiple Myeloma

Abstract

The aim of this study was to investigate whether the specific T cell response against the multiple myeloma Ag HM1.24 is enhanced by the immunomodulatory drug lenalidomide (Revlimid). Ag-specific CD3+CD8+ T cells against the HM1.24 Ag were expanded in vitro by dendritic cells in 29 healthy donors and 26 patients with plasma cell dyscrasias. Ag-specific activation was analyzed by IFN-γ, granzyme B, and perforin secretion using ELISA, ELISPOT assay, and intracellular staining, and generation of Ag-specific T cells was analyzed by tetramer staining. Expression of T cell maturation markers (CD45RA, CD45R0, CCR7, and CD28) was investigated by flow cytometry. We found that activation of HM1.24-specific T cells from healthy donors and patients with plasma cell dyscrasias was enhanced significantly by lenalidomide and furthermore that the impact of lenalidomide on T cells depends on the duration of the exposure. Notably, lenalidomide supports the downregulation of CD45RA on T cells upon activation, observed in healthy donors and in patients in vitro and also in patients during lenalidomide therapy in vivo. We showed for the first time, to our knowledge, that lenalidomide enhances the Ag-specific activation of T cells and the subsequent downregulation of CD45RA expression of T cells in vitro and in vivo.

Expansion of Polyfunctional HIV-Specific T Cells upon Stimulation with mRNA Electroporated Dendritic Cells in the Presence of Immunomodulatory Drugs

“…In the presence of IMiDs, we observed enhanced proliferation and cytokine production by HIV-specific CD8 ϩ T cells stimulated with dendritic cells, which is in accordance with previously published studies showing a costimulatory effect of IMiDs on antigenspecific T-cell responses (27,35,41). Furthermore, we found increased numbers of CD8 ϩ T cells degranulating (CD107a ϩ ), expressing perforin, and showing a high degree of functionality (i.e., expressing Ն3 of the following factors: the cytokines IFN-␥, TNF-␣, and IL-2 and the chemokine MIP-1␤) upon in vitro addition of IMiDs.…”

“…Although the addition of IMiDs reduced the proliferation of HIV-specific CD4 ϩ T cells, it resulted in higher percentages of polyfunctional CD4 ϩ T cells. Thalidomide and its IMiD analogues were previously shown to be strong costimulators of naïve and memory T-cell responses, including virus-specific CD8 ϩ T-cell responses (27,35,41). Although the mechanism whereby these agents trigger T cells is not completely understood, it has been shown that lenalidomide induces tyrosine phosphorylation of CD28 on T cells, resulting in the activation of nuclear factor B (NF-B) (35).…”

Treatment with lenalidomide induces immunoactivating and counter-regulatory immunosuppressive changes in myeloma patients

“…A decreased expression of CD45RA has also been associated with lenalidomide treatment by Neuber et al [23], who investigated the differentiation of T cells from MM and MGUS patients in vitro and in vivo. They also observed an increased antigenspecific activity within the T cell pool in the presence of lenalidomide but did not differentiate subsets further within the CD45RA -population.…”

The immunotherapy era of myeloma: monoclonal antibodies, vaccines, and adoptive T-cell therapies

“…67 Further evidence of these immunomodulatory properties has been discussed above in reference to the emerging combination with tumor targeting monoclonal antibodies, elotuzumab and daratumumab, where Len significantly provided or added antimyeloma activity, respectively, 29,36,68 as well as PD-1 blockade that went from no activity to a 50% response rate. 51,69 The overall explanation for Len-based enhanced immunogenicity is likely multifactorial and includes T-cell activation through increased tyrosine kinase activity of the CD28 receptor, 70 downregulation of CD45RA on T cells, 71 and downregulation of SOCS1 on the stromal elements of the tumor microenvironment.…”