T cells in chronic lymphocytic leukemia display dysregulated expression of immune checkpoints and activation markers

Haematologica. 2017 Mar;102(3):562-572. doi: 10.3324/haematol.2016.151100. Epub 2016 Dec 7.

Abstract

Chronic lymphocytic leukemia is characterized by impaired immune functions largely due to profound T-cell defects. T-cell functions also depend on co-signaling receptors, inhibitory or stimulatory, known as immune checkpoints, including cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and programmed death-1 (PD-1). Here we analyzed the T-cell phenotype focusing on immune checkpoints and activation markers in chronic lymphocytic leukemia patients (n=80) with different clinical characteristics and compared them to healthy controls. In general, patients had higher absolute numbers of CD3+ cells and the CD8+ subset was particularly expanded in previously treated patients. Progressive patients had higher numbers of CD4+ and CD8+ cells expressing PD-1 compared to healthy controls, which was more pronounced in previously treated patients (P=0.0003 and P=0.001, respectively). A significant increase in antigen-experienced T cells was observed in patients within both the CD4+ and CD8+ subsets, with a significantly higher PD-1 expression. Higher numbers of CD4+ and CD8+ cells with intracellular CTLA-4 were observed in patients, as well as high numbers of proliferating (Ki67+) and activated (CD69+) CD4+ and CD8+ cells, more pronounced in patients with active disease. The numbers of Th1, Th2, Th17 and regulatory T cells were substantially increased in patients compared to controls (P<0.05), albeit decreasing to low levels in pre-treated patients. In conclusion, chronic lymphocytic leukemia T cells display increased expression of immune checkpoints, abnormal subset distribution, and a higher proportion of proliferating cells compared to healthy T cells. Disease activity and previous treatment shape the T-cell profile of chronic lymphocytic leukemia patients in different ways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Biomarkers
  • Biomarkers, Tumor*
  • CTLA-4 Antigen / genetics
  • CTLA-4 Antigen / metabolism
  • Case-Control Studies
  • Chromosome Aberrations
  • Disease Progression
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Gene Expression Regulation, Leukemic*
  • Humans
  • Immunomodulation / genetics*
  • Immunophenotyping
  • Leukemia, Lymphocytic, Chronic, B-Cell / diagnosis
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics*
  • Leukemia, Lymphocytic, Chronic, B-Cell / immunology*
  • Leukemia, Lymphocytic, Chronic, B-Cell / therapy
  • Lymphocyte Count
  • Male
  • Middle Aged
  • Mutation
  • Phenotype
  • Prognosis
  • Programmed Cell Death 1 Receptor / genetics
  • Programmed Cell Death 1 Receptor / metabolism
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocyte Subsets / metabolism*
  • Tumor Necrosis Factor Receptor Superfamily, Member 9 / genetics
  • Tumor Necrosis Factor Receptor Superfamily, Member 9 / metabolism

Substances

  • Biomarkers
  • Biomarkers, Tumor
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Programmed Cell Death 1 Receptor
  • Tumor Necrosis Factor Receptor Superfamily, Member 9