Ibrutinib protects T cells in patients with CLL from proliferation-induced senescence

Abstract Background The 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 improvement...

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Autores principales:	Joanne E. Davis, Chia Sharpe, Kylie Mason, Constantine S. Tam, Rachel M. Koldej, David S. Ritchie
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Chronic Lymphocytic Leukaemia Bruton’s tyrosine kinase inhibitors T cells Proliferation Senescence Medicine R
Acceso en línea:	https://doaj.org/article/72b9726b70ce4860bc6b28377c17d44e
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spelling	oai:doaj.org-article:72b9726b70ce4860bc6b28377c17d44e2021-11-28T12:06:39ZIbrutinib protects T cells in patients with CLL from proliferation-induced senescence10.1186/s12967-021-03136-21479-5876https://doaj.org/article/72b9726b70ce4860bc6b28377c17d44e2021-11-01T00:00:00Zhttps://doi.org/10.1186/s12967-021-03136-2https://doaj.org/toc/1479-5876Abstract Background The 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. Methods In 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. Results Similar 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. Conclusions Collectively, 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.Joanne E. DavisChia SharpeKylie MasonConstantine S. TamRachel M. KoldejDavid S. RitchieBMCarticleChronic Lymphocytic LeukaemiaBruton’s tyrosine kinase inhibitorsT cellsProliferationSenescenceMedicineRENJournal of Translational Medicine, Vol 19, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Chronic Lymphocytic Leukaemia Bruton’s tyrosine kinase inhibitors T cells Proliferation Senescence Medicine R
spellingShingle	Chronic Lymphocytic Leukaemia Bruton’s tyrosine kinase inhibitors T cells Proliferation Senescence Medicine R Joanne E. Davis Chia Sharpe Kylie Mason Constantine S. Tam Rachel M. Koldej David S. Ritchie Ibrutinib protects T cells in patients with CLL from proliferation-induced senescence
description	Abstract Background The 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. Methods In 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. Results Similar 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. Conclusions Collectively, 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.
format	article
author	Joanne E. Davis Chia Sharpe Kylie Mason Constantine S. Tam Rachel M. Koldej David S. Ritchie
author_facet	Joanne E. Davis Chia Sharpe Kylie Mason Constantine S. Tam Rachel M. Koldej David S. Ritchie
author_sort	Joanne E. Davis
title	Ibrutinib protects T cells in patients with CLL from proliferation-induced senescence
title_short	Ibrutinib protects T cells in patients with CLL from proliferation-induced senescence
title_full	Ibrutinib protects T cells in patients with CLL from proliferation-induced senescence
title_fullStr	Ibrutinib protects T cells in patients with CLL from proliferation-induced senescence
title_full_unstemmed	Ibrutinib protects T cells in patients with CLL from proliferation-induced senescence
title_sort	ibrutinib protects t cells in patients with cll from proliferation-induced senescence
publisher	BMC
publishDate	2021
url	https://doaj.org/article/72b9726b70ce4860bc6b28377c17d44e
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Ibrutinib protects T cells in patients with CLL from proliferation-induced senescence

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