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

Sci Rep. 2020 Nov 30;10(1):20846. doi: 10.1038/s41598-020-77941-y.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Bone Marrow / immunology
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • Female
  • Granzymes / analysis
  • Granzymes / metabolism
  • Humans
  • Immunophenotyping / methods
  • Interferon-gamma / analysis
  • Interferon-gamma / metabolism
  • Male
  • Middle Aged
  • Multiple Myeloma / genetics
  • Multiple Myeloma / immunology*
  • Programmed Cell Death 1 Receptor / immunology*
  • Programmed Cell Death 1 Receptor / metabolism
  • T-Lymphocyte Subsets / immunology

Substances

  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Interferon-gamma
  • Granzymes