Сибирский онкологический журнал (Feb 2023)

Common Ɣ-chain cytokine receptors as functional phenotype markers of PD-1and TIM-3-positive T cells in multiple myeloma

  • E. V. Batorov,
  • V. A. Aristova,
  • G. Yu. Ushakova,
  • S. A. Sizikova,
  • V. V. Denisova,
  • E. Ya. Shevela,
  • A. A. Ostanin,
  • E. R. Chernykh

DOI
https://doi.org/10.21294/1814-4861-2023-22-1-43-54
Journal volume & issue
Vol. 22, no. 1
pp. 43 – 54

Abstract

Read online

T cells expressing checkpoint receptors PD-1, TIM-3 etc., are potential targets for monoclonal antibody immunotherapy in multiple myeloma (MM). However, checkpoint expressing T cell compartment includes different subsets, and their dysregulation following anti-checkpoint therapy can lead to the development of adverse events.The aim of this study was to evaluate activation markers – homeostatic cytokine receptors and transcription factors expressed by PD-1and TIM-3-positive T cells.Material and Methods. Relative counts of circulating PD-1and/or TIM-3-positive and negative T cells expressing common ɣ-chain cytokine receptors CD25, CD122, CD127, phosphorylated STAT5, and transcription factor EOMES associated with T cell exhaustion were studied using flow cytometry in 17 healthy donors, 22 MM patients with remission and 7 MM patients with progressive disease.Results. T cells expressing PD-1 and/or TIM-3 inhibitory checkpoint receptors in MM patients consisted of CD25+EOMESactivated cells, CD4+CD25+CD127-FOXP3+ regulatory T cells (Treg), CD4+CD25-EOMES+ dysfunctional cells. CD25+ T cells from healthy donors and MM patients, regardless of the expression of the studied checkpoint receptors, were EOMES-negative. No such association was found for CD122 and CD127 cytokine receptors. EOMES is a marker of T cell exhaustion for CD4+ T cells, but not for CD8+ T cells, in which it is more associated with activation. The proportion of CD4+ Tregs among circulating PD-1+ and TIM-3+ T cells was relatively low. A higher content of cytokine receptors in the population of TIM-3+ T cells may indicate the predominant involvement of TIM-3 in the control of homeostatic proliferation of mature T cells under lymphopenic conditions, while the expression of PD-1 may be more associated with the regulation of activation through T cell receptor. PD-1+ and/or TIM-3+ levels of activated, dysfunctional, and regulatory T cells can potentially be used to predict the safety and efficacy of targeted immunotherapy.

Keywords