Control of chronic lymphocytic leukemia development by clonally-expanded CD8+ T-cells that undergo functional exhaustion in secondary lymphoid tissues

TBET‐expressing Th1 CD4+T cells accumulate in chronic lymphocytic leukaemia without affecting disease progression in Eµ‐TCL1 mice

“…Alterations of T cell numbers and their subset distribution have been described for CLL patients in comparison to healthy controls (HC). Among these, increased numbers of blood T cells as well as a decrease of the CD4:CD8 ratio mainly due to higher numbers of CD8 + T cells were reported, results that were confirmed by our study (Catovsky et al , ; Herrmann et al , ; Platsoucas et al , ; Hanna et al , ). The role of CD4 + helper T cells in CLL is controversial, as these cells were shown to support survival and growth of CLL cells, but are also known to support adaptive immune control of tumours (Bagnara et al , ; Os et al , ; Burgler et al , ).…”

“…This revealed rather stable frequencies of Th1 and Th2 subsets in individual patients over time with only one case (CLL149) out of six patients that showed an increase in the percentage of CD4 + T cells expressing IFNγ, IL‐4 or TBET at one of the analyzed time points (Fig B–D). Given that CLL is known to be associated with immunodeficiency, this could be easily explained by a transient viral infection of this patient, even though we have no clinical information on that (Ravandi & O’Brien, ; Hanna et al , ). In accordance, the master transcriptional regulators TBET (Fig D) and GATA3 (Fig E) revealed similar results, suggesting that frequencies of T‐helper subsets are overall stable during disease course of CLL patients, lacking clinical signs of progressive disease.…”

“…This is in line with the observation that CLL cells are dependent on extracellular stimuli that trigger B cell receptor, Toll‐like receptor or cytokine receptor signalling (Hanna et al , ; Gimenez et al , ). In contrary, we recently showed that neutralizing IFNγ via injections of blocking antibodies in the TCL1 AT mouse model resulted in faster leukaemia progression in these mice (Hanna et al , ). As IFNγ is a key cytokine for the activation of cytotoxic T cells, this previous study highlights the relevance of adaptive immune control in CLL.…”

Selective BTK inhibition improves bendamustine therapy response and normalizes immune effector functions in chronic lymphocytic leukemia

“…Importantly, we did not detect a significant decrease in the percentage of effector CD8 + T‐cells (Fig. b ), which have been recently described to be specifically enriched with oligoclonal T‐cells which possess anti‐tumor functions . We further analyzed whether CC‐292 impacts on the functional capacity of T‐cells.…”

“…6b), which have been recently described to be specifically enriched with oligoclonal T-cells which possess anti-tumor functions. 32 We further analyzed whether CC-292 impacts on the functional capacity of T-cells. Besides a slight reduction in the percentage of IFNγ-producing CD4 + CD44 + T-cells, CC-292-treated mice showed no significant differences in the production of effector cytokines, such as IFNγ, TNFα, or IL-2 by neither antigen-experienced CD4 + CD44 + T-cells nor effector CD8 + T-cells, upon ex vivo stimulation ( Fig.…”