title: Expansion of a CD8(+)PD-1(+) replicative senescence phenotype in early stage CLL patients is associated with inverted CD4:CD8 ratios and disease progression.
abstract: OBJECTIVE
  Patients with chronic lymphocytic leukemia (CLL) display immune deficiency that is most obvious in advanced stage disease. Here we investigated whether this immune dysfunction plays a pathologic role in the progression of early stage disease patients.
  
  
  METHODS
  We carried out eight-color immunophenotyping analysis in a cohort of 110 untreated early stage CLL patients and 22 age-matched healthy donors and correlated our findings with clinical outcome data.
  
  
  RESULTS
  We found a significant reduction in naive CD4(+) and CD8(+) T cells in CLL patients. Only the CD4(+) subset showed significantly increased effector memory cells (T(EM) and T(EMRA)) in the whole cohort (P = 0.004 and P = 0.04, respectively). However, patients with inverted CD4:CD8 ratios (52 of 110) showed preferential expansion of the CD8 compartment, with a skewing of CD8(+) T(EMRA) (P = 0.03) coupled with increased percentage of CD57(+)CD28(-)CD27(-) T cells (P = 0.008) and PD-1 positivity (P = 0.027), consistent with a replicative senescence phenotype. Furthermore, inverted CD4:CD8 ratios were associated with shorter lymphocyte doubling time (P = 0.03), shorter time to first treatment (P = 0.03), and reduced progression-free survival (P = 0.005).
  
  
  CONCLUSIONS
  Our data show that the emergence of CD8(+)PD-1(+) replicative senescence phenotype in early stage CLL patients is associated with more aggressive clinical disease. Importantly, these findings were independent of tumor cell prognostic markers and could not be accounted for by patient age, changes in regulatory T-cell frequency, or cytomegalovirus serostatus (n = 217).
authors.affiliation: Department of Infection, Cardiff University, Wales, UK.
authors.forename: Claudia
authors.initials: C
authors.lastname: Nunes
authors.forename: Ryan
authors.initials: R
authors.lastname: Wong
authors.forename: Malcolm
authors.initials: M
authors.lastname: Mason
authors.forename: Chris
authors.initials: C
authors.lastname: Fegan
authors.forename: Stephen
authors.initials: S
authors.lastname: Man
authors.forename: Chris
authors.initials: C
authors.lastname: Pepper
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002469:Cell Separation; D016922:Cellular Senescence / Q000276:immunology; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D016130:Immunophenotyping; D053208:Kaplan-Meier Estimate; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000276:immunology* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011379:Prognosis; D061026:Programmed Cell Death 1 Receptor / Q000096:biosynthesis / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
chemical_list: C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor