The expression of PD-1 alone by T cells is associated with cell activation while the co-expression of TIM-3 indicates exhausted subsets both in peripheral blood and bone marrow of multiple myeloma patients

Abstract

Abstract Background Multiple myeloma (MM) is a lymphoid neoplasm characterized by the accumulation of malignant clones of plasma cells, usually within the bone marrow (BM). Despite the increase of T cells expressing inhibitory signal molecules (ISMs) — PD-1, TIM-3 etc. — having been described in MM, the first results of anti-PD-1 therapy for MM remain modest. ISMs are expressed on T cells and modulate the functional activity. A stable expression of ISMs on T cells is associated with T cell exhaustion, the condition of severe decrease of both cytotoxicity and cytokine secretion. At the same time, ISMs are also expressed by activated T cells. We studied the expression of PD-1 and TIM-3 by circulating and bone marrow (BM) T cells as a manifestation of T cell exhaustion treated MM patients. Methods Peripheral blood (PB) and BM samples of 45 MM patients were obtained during routine diagnostic procedures. The expression of PD-1 and TIM-3 by CD4+ and CD8+ T cells, intracellular production of IFNγ and intracellular expression of Ki-67 by T cells and Granzyme B production by CD8+ T cells were assessed using flow cytometry. Results Relative counts of PD-1+ subset of CD8+ T cells and both PD-1+ and TIM-3+ subsets of CD4+ T cells were higher in BM compared with PB. BM samples also contained higher amounts of double-positive PD-1+TIM-3+ subsets of CD8+ and CD4+ T cells compared with PB. Percentage of PB CD8+PD-1+, CD4+PD-1+, CD4+TIM-3+, CD8+PD-1+TIM-3+ and CD4+PD-1+TIM-3+ T cells correlated with the content of respective subsets in BM. Both PB and BM CD8+PD-1+ and CD4+PD-1+ T cells of MM patients retain a cytotoxic, proliferative and cytokine-producing potential appropriate to PD-1-negative subsets. On the contrary, the functional activity of CD8+PD-1+TIM-3+ and CD4+PD-1+TIM-3+ T cells was significantly reduced compared with PD-1- and TIM-3-negative subsets. Conclusion PD-1+ T cells in MM patients are related to activated rather than exhausted populations. T cell exhaustion is associated with cells co-expressing PD-1 and TIM-3. It is recommended to evaluate T cell subsets co-expressing PD-1, TIM-3 and other ISMs, and to study their functional properties. Legal entity responsible for the study The authors. Funding The Russian Science Foundation (grant no. 18-75-00050). Disclosure All authors have declared no conflicts of interest.