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 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.

Targeted Agents in the Treatment of Indolent B-Cell Non-Hodgkin Lymphomas

“…While this may account for some observed toxicities, these changes may also play a role in therapeutic activity. Inhibition of ITK, for example, is associated with broader immunologic changes, including skewing towards a Th1 CD4+ phenotype and improved T-cell expansion and fitness [ 15 , 16 , 17 ]. Ibrutinib first came to prominence in studies of CLL, where it was demonstrated to induce high rates of overall response in both previously treated and untreated patients [ 18 , 19 ].…”

Effects of ibrutinib on T-cell immunity in patients with chronic lymphocytic leukemia

“…Accumulating data have demonstrated that ibrutinib can directly inhibit the expression of inhibitory receptors (21,44,50,82,84) and reduce the number of terminally differentiated T cells, such as TLTA, Texh, T EM , and T EMRA cells (79, 84) but remain naïve T cells (79). Niemann et al found that PD-1 expression significantly decreased at 4 weeks after ibrutinib treatment in CLL patients (34).…”

“…Nevertheless, in CLL patients, CD4 + T cells stimulate CLL cell survival and proliferation by secreting multiple chemokines/cytokines and through direct contact with the CD40 ligand (27,36,94), and CD8 + T cells are persistently activated and expanded within the CLL microenvironment and gradually become pseudo-exhausted (5,50,52), finally resulting in T-cell immune tolerance and the loss of their anti-tumor activity (27), which has been reported to be causative of the poor response to CAR-T cell therapies for CLL patients (95-97). Additionally, due to the damaged structure of effector T cells and the poor antigen presentation function of CLL cells, the formation of immune synapses between T and CLL cells is impaired (84,98).…”

“…For instance, ibrutinib promotes immune synapse formation between T and tumor cells and restores immune function by enhancing F-actin polarization and protein tyrosine phosphorylation (99, 100). Moreover, long-term ibrutinib therapy is likely to reverse the pseudo-exhaustion of T cells and promote the activity of effector T cells in CLL patients by inhibiting ITK activity and reducing the expression of inhibitory receptors (53,83,84). Additionally, ibrutinib directly and indirectly blocks the interaction between CLL and T cells by inhibiting cytokine networks and reducing tumor burden (34).…”

In Vitro and In Vivo Models of CLL–T Cell Interactions: Implications for Drug Testing

“…This is underscored by the observations that proliferating CLL cells in vivo are located close to activated helper T cells [9][10][11] and that in vitro CLL cells virtually never spontaneously divide [12,13] until they are provided with factors produced by helper T cells, such as CD40L, IL21, and IL4 [11,14,15]. Moreover, changes in the T-cell repertoire have been associated with CLL prognosis [14] and are affected by targeted therapy [15,16]. The T cells of patients with CLL also reveal functional differences with those of the healthy population [17], such as the relative sizes of T-cell subsets [18], the presence of specific clonotypes [19], exhausted phenotypes [20], and lower CD40L levels [7].…”