CD8+ CD28 null T Cell Expansion Impairs Lenalidomide Immunomodulatory Function in Myelodysplastic Syndrome

Abstract 1117 Lenalidomide, a thalidomide analog, is known to induce high rates of transfusion independence in Myelodysplastic Syndrome (MDS) patients harboring a commonly deleted region on chromosome 5q (del(5q)). Erythroid response is also seen in 20–30% of low-risk, non-del(5q) patients, although the mechanism of response is incompletely understood. Lenalidomide is a potent immunomodulating agent and hematopoietic response has been linked to increased lymphocyte infiltration in the bone marrow and improved T cell and NK cell proliferation/function. Lenalidomide9s effect on the erythroid compartment is well documented, but the effect of lenalidomide on the immune compartment, and the relationship between the T cell compartment and erythroid response in vivo in MDS is not known. We therefore examined 23 T cell parameters before lenalidomide treatment and correlated them to hematologic response. We found that patients who fail lenalidomide therapy had higher CD8 + Terminal Effector Memory (TEM) T cells than did responders (p=0.02). TEM cells express CD45RA, have variable expression of the CD45RO memory marker and loss of L-selectin (CD62L) lymph node homing receptor. Interestingly, T cells within the TEM compartment are uniformly CD28 deficient (CD28 null ). Lenalidomide has been shown by us and others to increase the proliferation and function of T cells by providing co-stimulation (LeBlanc et al. 2004, Blood) through CD28, so CD28 expression may be important for immunomodulatory response. We found that MDS patients non-responsive to lenalidomide had an overall increase in CD4 (p=0.0195) and CD8 (p=0.0317) CD28 null T cells, as well as an increase in CD28 null cells (p=0.0159) within the TEM compartment compared to hematologic responders. To determine if CD28 expression is necessary for lenalidomide action in T cells, we sorted healthy donor T cells into CD8 + CD28 + and CD8 + CD28 − populations, and found that lenalidomide-induced proliferation and interleukin-2 (IL-2) production were completely ablated within the CD28 null subset. Because CD28 null T cells displayed less proliferation (p in vivo , we therefore used shRNA to knockdown CD28 in healthy (CD28 + ) T cells and determined the functional response of these cells to lenalidomide. With CD28 knockdown, lenalidomide produced significantly less IL-2 compared to CD28+ controls (p Disclosures: List: Celgene: Consultancy. Epling-Burnette: Celgene: Research Funding.