ZAP-70 expression is associated with increased CD4 central memory T cells in chronic lymphocytic leukemia: cross-sectional study

Abstract

BackgroundAlthough chronic lymphocytic leukemia is basically a B cell disease, its pathophysiology and evolution are thought to be significantly influenced by T cells, as these are probably the most important interaction partner of neoplastic B cells, participating in their expansion, differentiation and survival. Chronic lymphocytic leukemia B cells may also drive functional and phenotypic changes of non-malignant T cells. There are few data about the association between memory T cells and prognosis, especially related to ZAP-70, a common reliable surrogate of the gold standard chronic lymphocytic leukemia prognostic markers.ObjectiveThe aim of this study was to investigate whether the expression of ZAP-70 in chronic lymphocytic leukemia patients is associated with abnormal patterns of the distribution of naïve and memory T cells related to crosstalk between these cells.MethodsIn this cross-sectional, controlled study, patients with chronic lymphocytic leukemia were compared with healthy blood donors regarding the expression of ZAP-70 and the distribution of naïve and memory T cell subsets in peripheral blood as measured by flow cytometry.ResultsZAP-70 positive patients presented an increased frequency and absolute number of central memory CD4+ T cells, but not CD8+ T cells, compared to ZAP-70 negative patients and age-matched apparently healthy donors.ConclusionsBecause central memory CD4+ T cells are located in lymph nodes and express CD40L, we consider that malignant ZAP-70-positive B cells may receive beneficial signals from central memory CD4+ T cells as they accumulate, which could contribute to more aggressive disease.

CD markers variations in chronic lymphocytic leukemia: New insights into prognosis

“…ZAP‐70, a tyrosine kinase, can be abnormally expressed on a number of B‐cells from CLL patients (Table ; Krober et al, ). Overexpression of ZAP‐70 (>20%) in CLL patients can be associated with shorter time to treatment (Hallek & Group, ; Mougalian & O'Brien, ), which can lead to decreasing naive CD4 + T‐cells and increasing central memory CD4 + T‐cells (Correia et al, ). Memory CD4 + T‐cells can play an essential role in increasing the life span of malignant B‐cells by producing cytokines such as IL‐4 and interferon γ (IFN‐γ; Buschle et al, ; Panayiotidis, Ganeshaguru, Jabbar, & Hoffbrand, ).…”

“…Memory CD4 + T-cells can play an essential role in increasing the life span of malignant B-cells by producing cytokines such as IL-4 and interferon γ (IFN-γ;Buschle et al, 1993;Panayiotidis, Ganeshaguru, Jabbar, & Hoffbrand, 1993). Moreover, these cells can migrate toward LN and interact with B-cells through CD40L and CXCR5, contributing to longer survival of BCR signaling as well as increasing the survival and expansion of neoplastic B-cells (Figure2;Correia et al, 2018). ZAP-70 expression can also be related to poor prognostic factors (…”

“…with shorter time to treatment(Hallek & Group, 2008;Mougalian & O'Brien, 2011), which can lead to decreasing naive CD4 + T-cells and increasing central memory CD4 + T-cells(Correia et al, 2018). Memory CD4 + T-cells can play an essential role in increasing the life span of malignant B-cells by producing cytokines such as IL-4 and interferon γ (IFN-γ;Buschle et al, 1993;Panayiotidis, Ganeshaguru, Jabbar, & Hoffbrand, 1993).…”

ZAP-70 Shapes the Immune Microenvironment in B Cell Malignancies

“…Mounting evidence indicates that the ZAP-70 expressed in tumor cells has ramifications for the composition of immune cells in the microenvironment, especially for the number of infiltrating T cells. In studies comparing the immune-phenotype of ZAP-70 positive and ZAP-70 negative CLL patients, tumor ZAP-70 expression was associated with increased CD4 central memory T cells and CD3/CD69+ T cells with decreased CD4/CD8 ratio in the peripheral blood (40)(41)(42). However, since high ZAP-70 expression is normally observed in only a subpopulation of CLL cells and varies substantially between patients, it is possible that subtle changes in different T cell populations between ZAP-70 positive and negative patients are partly impacted by inconsistencies in the definition of ZAP-70 positive in these studies.…”