Ibrutinib enhances the bias of T cell responses towards staphylococcal superantigens sustaining inflammation in chronic lymphocytic leukaemia

Chronic lymphocytic leukaemia (CLL) is an uncurable haematological malignancy and is associated with significant infection morbidity. Bruton's tyrosine-kinase inhibitors (<i>e.g.</i>, ibrutinib) have improved disease outcomes, but severe infections and poor immunization responses afflict patients. Recently, carriage of the endemic <i>Staphylococcus aureus</i> (SA) was associated with lymphocytosis and decreased survival in CLL patients. We then hypothesized that exposure to staphylococcal superantigens (SAgs), known to promote hyper-inflammatory responses, impairs immunity and increases severe infection risk in CLL patients. Herein, we evaluate the reactivity of T cells and CLL cells to SA SAgs, in cultures derived from ibrutinib-treated and untreated CLL patients. We found that ibrutinib-treated patients had less naive CD8+ T cells (p=0.0348), more checkpoint receptor (TIM-3) expression in memory T cells (p<0.0001), and lower IFNγ/cytokine responses in patient T cells (p≤0.0298). Exposure to SA SAg further increased the accumulation of memory T cells with an exhaustion-phenotype, preferentially in cultures derived from ibrutinib-treated patients (p≤0.0350). Nevertheless, staphylococcal SAgs could not induce regulatory T cells from CLL patients inasmuch as healthy donors (p≤0.0461) and this was associated with accumulation of inflammatory T cells. Significantly, SAg-exposure enhanced inflammatory activation of CLL tumour cells, which acquired CD38, CD40, CD86, while downregulating CD27 (p≤0.005), even in cultures from ibrutinib-treated CLL patients. Thus, we suggest that environmental SAg-exposure promotes the accumulation of pseudo-exhausted T cells, which induce/sustain tumour cell activation, not counteracted by ibrutinib. Our study critically helps understand the chronic inflammatory milieu in CLL patients, with implications for infection morbidity, disease aetiology and future interventions.