Abstract
Lenalidomide is a potent anti-myeloma drug with immunomodulatory properties. It is increasingly used in a low-dose maintenance setting to prolong remission duration after standard treatment. Data on the in vivo effects of lenalidomide are scarce and sometimes different from the well-described in vitro effects. We therefore evaluated the numerical, phenotypical and functional impact of lenalidomide maintenance on several immune cell types in a cohort of seventeen homogeneously treated myeloma patients achieving a low residual myeloma burden after a bortezomib based-induction followed by autologous stem cell transplantation. Lenalidomide maintenance: 1) increased the fraction of naïve CD8+ T cells and several memory T-cell subsets, 2) reduced the numbers of terminal effector CD8+ T cells, 3) resulted in a higher expression of co-stimulatory molecules on resting T cells and of the inhibitory checkpoint molecules LAG-3 on CD4+ T cells and TIM-3 on CD4+ and CD8+ T cells, 4) reduced the number of TIGIT+ CD8+ T cells, 5) increased the number of regulatory T cells with a phenotype associated with strong suppressive capacity. Purified CD8+ T cells showed increased and more polyfunctional recall viral responses. However, PBMC responses were not enhanced during lenalidomide maintenance and CD4+ T-cell responses specific for the myeloma-associated antigen MAGE-C1 even tended to become lower. We conclude that lenalidomide maintenance after autologous stem cell transplantation has complex pleotropic effects on the immune environment. Immune interventions such as anti-myeloma vaccination should include measures to tackle an expanded inhibitory Treg compartment.
Highlights
Maintenance treatment with the immunomodulatory drug (IMiD) lenalidomide prolongs progression-free and overall survival in multiple myeloma (MM) patients after autologous stem cell transplantation (ASCT)
The pre-LEN timepoint was assessed at a median of 18.1 weeks, LEN was started at a median of 25.6 weeks and the LEN timepoint was assessed at a median of 41.3 weeks, all after ASCT
The positive effect of lenalidomide maintenance on PFS and survival after ASCT is generally ascribed to immune modulation of the myeloma microenvironment
Summary
Maintenance treatment with the immunomodulatory drug (IMiD) lenalidomide prolongs progression-free and overall survival in multiple myeloma (MM) patients after autologous stem cell transplantation (ASCT). An important mechanism of action of lenalidomide is its effect on the immune system, which is heavily disrupted in MM patients. Various studies have demonstrated the in vitro immunomodulatory effects of lenalidomide: increased natural killer (NK) cell cytotoxicity [1], improved functionality of invariant NKT cells [2] and T-cell co-stimulatory capacity [1, 3], resulting in broad and polyfunctional antigen-specific T-cell responses with a high antigen sensitivity [4, 5]. The addition of lenalidomide to T-cell cultures results in a decreased www.oncotarget.com expression of the inhibitory immune checkpoint molecule programmed death protein 1 (PD-1) while potentiating responses to a dendritic cell (DC)/myeloma fusion vaccine [6]. Lenalidomide inhibits the proliferation and T-cell suppressive function of regulatory T cells (Tregs) in vitro [5, 6, 9]
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