Lenalidomide (CC5013, Revlimid®) Alters a T Cell Homeostatic Check-Point in Patients with Myelodysplastic Syndrome (MDS).

Background: Myelodysplastic Syndromes (MDS) are a diverse group of myeloid malignancies that occur primarily in older individuals. Several distinct immunologic abnormalities have been described in MDS, including concurrent autoimmune diseases, inversion of CD4+ and CD8+ cell populations, and expansion hematopoietic inhibitory) CD8+ T cell clones. Suppression of hematopoiesis by T cells has been implicated in the pathogenesis of ineffective hematopoiesis in a select subpopulation of patients with response to immunosuppressive therapy. Immunologic abnormalities in MDS patients may relate to the process of immunologic aging associated with functional deterioration. Lenalidomide (CC5013, Revlimid®, Celgene Inc) is a member of a proprietary drug class known as immunomodulatory drugs (IMiDs) with strong and sustained hematological activity in MDS patients. The goal of this study was to investigate the in vitro and in vivo actions of lenalidomide on T cell immune functions and homeostasis in MDS patients.

Methods: Using peripheral blood mononuclear cells (PBMCs), we analyzed T cell subpopulations and function in 11 MDS patients and 12 controls of similar age. Naïve and memory CD4 and CD8 T cell sub-populations were segregated by expression of CD45RA and CD62L expression by flow cytometry. After antigen activation with anti-CD3-cross-linking and allogeneic dendritic cells (allo-DCs), T cell proliferation was assessed by Brdu incorporation in CD4+ and CD8+ T cells, and intracellular cytokines determined by flow cytometry. T cell receptor (TCR) repertoire skewing was determined by CDR3-length analysis on 53 patients. In vivo action of lenalidomide was evaluated in PBMCs from seven patients (4 erythroid complete responders and 3 non-responders) taken pre- and post-treatment.

Results: Patients with MDS had reduced T cell proliferation and impaired Th1 cytokine response after antigen stimulation compared to age-matched controls. No correlation was found between patient age and percentage of proliferating antigen-induced CD4− or CD8− T cells (r=0.13, p=0.6 and r=−0.17, p=0.5, respectively). Phenotype analysis showed that the percentage of CD4+ and CD8+/CD45RA+/CD62L+−naïve T cells were significantly reduced, whereas, CD4+ and CD8+/CD45RA−/CD62L−double-negative effector memory cells were significantly increased in MDS patients. Furthermore, 50% of MDS patients displayed a skewed T cell receptor repertoire that was not age-dependent. Of the MDS patients treated with lenalidomide, the four responders displayed a significant increase in antigen-induced T cell proliferation and increased Th1-type cytokine secretion, whereas no changes were observed in non-responders. Moreover, CD4+ (P=0.001) and CD8+ (P=0.06) T cells with a naïve phenotype increased accompanied by augmentation in the percentage of CD8+ central memory T cells (P=0.02); whereas, the percentage of CD4+ effector memory cells decreased (p=0.001) in lenalidomide responders but not in non-responders.

Conclusions: These data suggest that MDS patients possess multiple T cell defects including age-independent TCR repertoire skewing, reduction in naïve T cells, and accumulation of effector memory cells that are improved by lenalidomide. Our findings suggest hematopoietic response to lenalidomide may relate to a novel capacity to restore T cell homeostasis.