Abstract
BackgroundThe development of Bruton’s tyrosine kinase inhibitors (BTKi) for the treatment of chronic lymphocytic leukaemia (CLL) has provided a highly effective and relatively non-toxic alternative to conventional chemotherapy. Some studies have shown that BTKi can also lead to improvements in T cell immunity in patients despite in vitro analyses suggesting an immunosuppressive effect of BTKi on T cell function.MethodsIn this study, we examined both the in vitro effect and long-term in vivo effect of two clinically available BTKi, ibrutinib and zanubrutinib. Additional in vitro assessments were undertaken for a third BTKi, acalabrutinib. Immune subset phenotyping, cytokine secretion, T cell degranulation and proliferation assays were performed on peripheral blood mononuclear cells isolated from untreated CLL patients, and CLL patients on long-term (> 12 months) BTKi treatment.ResultsSimilar to prior studies we observed that long-term BTKi treatment normalises lymphocyte subset frequency and reduces PD-1 expression on T cells. We also observed that T cells from patients taken prior to BTKi therapy showed an abnormal hyper-proliferation pattern typical of senescent T cells, which was normalised by long-term BTKi treatment. Furthermore, BTKi therapy resulted in reduced expression of the T cell exhaustion markers PD-1, TIM3 and LAG3 in late generations of T cells undergoing proliferation.ConclusionsCollectively, these findings indicate that there are critical differences between the in vitro effects of BTKi on T cell function and the effects derived from long-term BTKi exposure in vivo. Overall long-term exposure to BTKi, and particularly ibrutinib, resulted in improved T cell fitness in part due to suppressing the abnormal hyper-proliferation of CLL T cells and the associated development of T cell senescence.
Highlights
Chronic lymphocytic leukaemia (CLL) is the most common adult leukaemia in the western world and is associated with significant perturbations of cellular and humoral immunity including an excess of terminallyDavis et al Journal of Translational Medicine (2021) 19:473 indicated for the treatment of relapsed chronic lymphocytic leukaemia (CLL), [4] more recently Bruton’s tyrosine kinase inhibitors (BTKi) has been incorporated as part of frontline therapy [5] and thereby represent an opportunity for chemotherapy-free treatment of CLL, potentially reducing the impact of lymphodepleting chemotherapy and promoting long-term preservation of immunity
T cells improve in number and function after long‐term BTKi exposure In order to examine the impact of BTKi on T cell function in CLL, peripheral blood samples taken at baseline and following long-term treatment (12–24 months) were analysed
CLL patients had low frequencies of CD4+ naïve T cells compared to healthy donors, which significantly increased after long-term zanubrutinib treatment (Additional file 1: Figure S4A– D)
Summary
Chronic lymphocytic leukaemia (CLL) is the most common adult leukaemia in the western world and is associated with significant perturbations of cellular and humoral immunity including an excess of terminallyDavis et al Journal of Translational Medicine (2021) 19:473 indicated for the treatment of relapsed CLL, [4] more recently BTKi has been incorporated as part of frontline therapy [5] and thereby represent an opportunity for chemotherapy-free treatment of CLL, potentially reducing the impact of lymphodepleting chemotherapy and promoting long-term preservation of immunity. Early observations in ibrutinib-treated patients suggested an immunosuppressive effect with increased opportunistic infections in heavily pre-treated patients with CLL who subsequently were treated with ibrutinib [14,15,16,17] These findings have been linked to the impairment of macrophage function by ibrutinib [18, 19] in addition to cumulative impairment of cellular immunodeficiency induced by prior therapies and/or persistent immune dysfunction exerted by the effects of the CLL microenvironment. We have demonstrated that long-term exposure to ibrutinib in vivo may return the T cell function of patients with advanced mantle cell lymphoma (MCL) to that of healthy donors [25] Overall, this improved T cell fitness following ibrutinib therapy may in turn be able to be exploited to improve the generation and efficacy of subsequent adoptive CAR-T cell therapy in CLL [26] or other B cell malignancies including MCL [27]. Some studies have shown that BTKi can lead to improvements in T cell immunity in patients despite in vitro analyses suggesting an immunosuppressive effect of BTKi on T cell function
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