Quantitative and functional characteristics of circulating and bone marrow PD-1- and TIM-3-positive T cells in treated multiple myeloma patients

The aim of the present work was to evaluate counts and functional properties of PD-1(+) and TIM-3(+) T cells in peripheral blood (PB) and bone marrow (BM) of multiple myeloma (MM) patients following the induction therapy. Sixty patients were enrolled in the study, CD4(+) and CD8(+) T cells expressing PD-1 and TIM-3, intracellular production of IFNγ and intracellular expression of Granzyme B were assessed. Relative counts of the majority of circulating PD-1(+), TIM-3(+) and PD-1(+)TIM-3(+) T cells were higher in MM patients with disease progression compared with individuals in remission. Frequencies of almost all evaluated PD-1(+) and TIM-3(+) T cell subsets were higher in BM samples compared with PB; circulating CD4(+)PD-1(+), CD8(+)PD-1(+), CD8(+)TIM-3(+), CD8(+)PD-1(+)TIM-3(+) T cells positively correlated with the same BM subsets. Circulating CD4(+) T cells, expressing PD-1 and TIM-3 (including co-expressing subset), as well as CD8(+)PD-1(+)TIM-3(+) T cells, and BM CD8(+)PD-1(+) T cells correlated with serum B2-M levels. Sufficient frequencies of GrB(+) and IFNγ(+) subsets in PD-1-expressing T cells indicated their retained functional properties. TIM-3-expressing T cells and double positive PD-1(+)TIM-3(+) populations showed diminished cytotoxic and cytokine-producing ability and therefore might be attributed to the exhausted compartment. To identify T cell exhaustion, it is necessary to evaluate T cells co-expressing PD-1, TIM-3 and other inhibitory signal molecules and to study their functional properties. Sustained functionality of PD-1-positive T cells may explain low efficacy and frequent immune-mediated adverse events during anti-PD-1 therapy in MM.