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

Davis, JE; Sharpe, C; Mason, K; Tam, CS; Koldej, RM; Ritchie, DS

Author(s): Davis, JE; Sharpe, C; Mason, K; Tam, CS; Koldej, RM; Ritchie, DS;
Details: Publication Year 2021-11-22,Volume 19,Issue #1,Page 473
Journal Title: Journal of Translational Medicine
Publication Type: Research article
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.
Keywords: Adenine/analogs & derivatives; Cell Proliferation; Humans; *Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy; Leukocytes, Mononuclear; Piperidines; Protein Kinase Inhibitors; T-Lymphocytes
Department(s): Haematology
PubMed ID: 34809665
Publisher's Version: https://doi.org/10.1186/s12967-021-03136-2
Open Access at Publisher's Site: https://doi.org/10.1186/s12967-021-03136-2
Terms of Use/Rights Notice: Refer to copyright notice on published article.

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Last Modified: 2026-01-28 12:33:28