BACKGROUND: Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the western world. This health problem is caused due to the accumulation of mature B-lymphocytes in the peripheral blood and bone marrow. In the course of cancer, CD4+ T cells become "exhausted" and characterized with poor effector functions and the expression of multiple inhibitory receptors. OBJECTIVE: To investigate the frequency and functional properties of exhausted CD4+ T lymphocytes in patients with CLL. METHODS: Peripheral blood mononuclear cells were obtained from 25 untreated CLL patients and 15 healthy volunteers. CLL patients were clinically classified according to the Rai staging system. The frequency of CD4+/Tim-3+/PD-1+ cells was obtained by flow cytometry. To evaluate cell proliferation and cytokine production, CD4+ T cells were isolated and stimulated with phytohemagglutinin and PMA/ionomycin. Concentrations of IL-2, IFN-γ, TNF-α, and IL-10 were measured in the culture supernatants of stimulated cells by the ELISA technique. RESULTS: The percentage of CD4+/Tim-3+/PD-1+ cells was significantly higher in CLL patients than that of healthy controls. CD4+ T cells from CLL patients showed lower proliferative responses, a lower production of IL-2, IFN-γ, and TNF-α, and a higher production of IL-10, compared to healthy controls. CD4+ T cells from CLL patients in advanced clinical stages showed more exhaustion features than those of early stages. CONCLUSION: Given that the exhaustion phase of T cells can be reversible, targeted blocking of immune inhibitory molecules could be a promising tool to restore the host immune responses against leukemic cells in CLL.
BACKGROUND:Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the western world. This health problem is caused due to the accumulation of mature B-lymphocytes in the peripheral blood and bone marrow. In the course of cancer, CD4+ T cells become "exhausted" and characterized with poor effector functions and the expression of multiple inhibitory receptors. OBJECTIVE: To investigate the frequency and functional properties of exhausted CD4+ T lymphocytes in patients with CLL. METHODS: Peripheral blood mononuclear cells were obtained from 25 untreated CLLpatients and 15 healthy volunteers. CLLpatients were clinically classified according to the Rai staging system. The frequency of CD4+/Tim-3+/PD-1+ cells was obtained by flow cytometry. To evaluate cell proliferation and cytokine production, CD4+ T cells were isolated and stimulated with phytohemagglutinin and PMA/ionomycin. Concentrations of IL-2, IFN-γ, TNF-α, and IL-10 were measured in the culture supernatants of stimulated cells by the ELISA technique. RESULTS: The percentage of CD4+/Tim-3+/PD-1+ cells was significantly higher in CLLpatients than that of healthy controls. CD4+ T cells from CLLpatients showed lower proliferative responses, a lower production of IL-2, IFN-γ, and TNF-α, and a higher production of IL-10, compared to healthy controls. CD4+ T cells from CLLpatients in advanced clinical stages showed more exhaustion features than those of early stages. CONCLUSION: Given that the exhaustion phase of T cells can be reversible, targeted blocking of immune inhibitory molecules could be a promising tool to restore the host immune responses against leukemic cells in CLL.
Authors: Anna Pawłowska; Dorota Suszczyk; Rafał Tarkowski; Roman Paduch; Jan Kotarski; Iwona Wertel Journal: Cancer Manag Res Date: 2020-10-07 Impact factor: 3.989
Authors: Alexandra M Miggelbrink; Joshua D Jackson; Selena J Lorrey; Ethan S Srinivasan; Jessica Waibl-Polania; Daniel S Wilkinson; Peter E Fecci Journal: Clin Cancer Res Date: 2021-06-14 Impact factor: 12.531