Targeting CD38 suppresses induction and function of T regulatory cells to mitigate immunosuppression in multiple myeloma

Purpose: We study CD38 levels in immunosuppressive CD4+CD25highFoxp3+ Tregs and further define immune modulating effects of a therapeutic CD38 monoclonal antibody (mAb) Isatuximab (Isa)/SAR650984 in multiple myeloma (MM). Experimental Design: We evaluated percentages of CD38-expressing subsets in Tregs from normal donors and MM patients. PBMCs were then treated with Isa with or without Lenalidomide (Len) or Pomalidomide (Pom) to identify their impact on percentage and immunosuppressive activity of Tregs on CD4+CD25- T cells (Tcons). We investigated the mechanism of increased Tregs in MM patients in ex vivo cocultures of MM cells with PBMCs or Tcons. Results: CD38 expression is higher on Tregs than Tcons from MM patients versus normal donors. CD38 levels and the percentages of CD38high Tregs are increased by Len and Pom. Isa preferentially decreases Treg and increases Tcon frequencies, which is enhanced by Pom/Len. Isa reduces Foxp3 and IL10 in Tregs and restores proliferation and function of Tcons. It augments MM cell lysis by CD8+ T and natural killer cells. Coculture of MM cells with Tcons significantly induces Tregs (iTregs), which express even higher CD38, CD25, and FoxP3 than natural Tregs. This is associated with elevated circulating CD38+ Tregs in MM patients vs. normal donors. Conversely, Isa decreases MM cell- and bone marrow stromal cell-induced iTreg by inhibiting both cell-cell contact and TGFBeta/IL10. Finally, CD38 levels correlate with differential inhibition by Isa of Tregs from MM vs normal donors. Conclusions:: Targeting CD38 by Isa can preferentially block immunosuppressive Tregs and thereby restore immune effector function against MM.