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

Purpose: 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.Experimental Design: 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 þ and CD8 þ T cells in CLL patients. Only the CD4 þ subset showed significantly increased effector memory cells (T EM and T EMRA ) in the whole cohort (P ¼ 0.004 and P ¼ 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 þ T EMRA (P ¼ 0.03) coupled with increased percentage of CD57 þ CD28 À CD27 À T cells (P ¼ 0.008) and PD-1 positivity (P ¼ 0.027), consistent with a replicative senescence phenotype. Furthermore, inverted CD4:CD8 ratios were associated with shorter lymphocyte doubling time (P ¼ 0.03), shorter time to first treatment (P ¼ 0.03), and reduced progression-free survival (P ¼ 0.005). Conclusions: Our data show that the emergence of CD8 þ PD-1 þ 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. Clin Cancer Res; 18(3); 678-87. Ó2011 AACR.

Blinatumomab induces autologous T-cell killing of chronic lymphocytic leukemia cells

“…16,19,[22][23][24][25] The precise role that different T-cell subsets play in the immunodeficiency of CLL remains undetermined but functional studies have identified defects in immune synapse formation, costimulatory/accessory molecule expression and cytokine release.…”

“…16,19,[22][23][24][25] The precise role that different T-cell subsets play in the immunodeficiency of CLL remains undetermined but functional studies have identified defects in immune synapse formation, costimulatory/accessory molecule expression and cytokine release. [15][16][17] Despite these problems, several T-cell-based therapeutic strategies have been tried in CLL including adoptive transfer of anti-CD3/anti-CD28 activated T cells, 26 T cells expressing chimeric antigen receptors, and vaccine therapy with dendritic cells pulsed with CLL-cell lysates.…”

B cell receptor usage correlates with the sensitivity to CD40 stimulation and the occurrence of CD4+ T cell clonality in chronic lymphocytic leukemia

“…T-cell exhaustion has been proposed as an important mechanism involved in CLL pathogenesis, 5,6,8 leading to a general hyporesponsiveness of T cells in CLL. As such, the clones observed in our study may be functionally silent and not necessarily provide relevant T-cell help for CLL.…”

“…As recent reports suggested T-cell exhaustion, a functional silencing of T cells, to be involved in the development of CLL, [5][6][7] we also assessed the expression of the exhaustion marker programmed death-1 (PD-1) on over-represented T cells. Thereby Figure 2F and Online Supplementary Table S3), suggesting that clonal T cells are likely to be an exhausted T-cell fraction.…”

Cytomegalovirus infection does not impact on survival or time to first treatment in patients with chronic lymphocytic leukemia

“…The mechanisms that underlie the reduction in immune competence are multifactorial but include hypogammaglobulinemia and T cell dysfunction 13. In addition, the burden of chronic infection and changes in the T cell repertoire are also important for overall prognosis in B‐CLL, and an inverted CD4:CD8 T cell ratio is associated with disease progression 14. The CD4:CD8 ratio is markedly lower in CMV seropositive individuals compared with those who remain uninfected, and this effect is particularly profound in patients with CLL.…”