PD-1 expression contributes to the functional impairment of NK cells in patients with B-CLL

Chronic lymphocytic leukaemia (B-CLL) is associated with immune suppression and functional impairment of NK cells, due partly to the reduced expression of activating receptors. We studied the profile of inhibitory checkpoint receptor expression on NK cells from patients with B-CLL. Single, dual and triple expression of the checkpoint receptors PD-1, CTLA-4, LAG-3 and CD96 was increased in patients compared to age-matched healthy controls. PD-1pos cells were present within the late differentiated CD56dim NK pool and showed strong downregulation of all activatory receptors whilst transcriptional profiles revealed a profile of strong receptor signalling. PD-1pos NK cells demonstrated impaired cytokine production and degranulation following target engagement and transfection of PD-1 into NK cell lines directed suppressed cytotoxic function. Importantly, blockade of PD-1:PD-L1 engagement acted to partially reverse these functional defects. These results reveal expression of inhibitory checkpoint receptors to be a new mechanism of NK cell dysfunction in patients with cancer and indicate a potential therapeutic role for single or combinatorial checkpoint blockade to boost immune function in patients with B-CLL.