PD-1 expression identifies activated and proliferating chronic lymphocytic leukemia cells and is a potential biomarker that informs response and resistance to BTK inhibitor therapy

Multiple signaling pathways have been implicated in promoting malignant B cell proliferation in chronic lymphocytic leukemia (CLL). Here we report that activated and proliferating CLL cells in circulation express the immune checkpoint PD-1. Circulating PD-1+ CLL cells upregulate genes associated with B cell receptor (BCR) and toll like receptor (TLR) signaling, and cell activation and proliferation. We demonstrate that BCR and TLR9 signaling induces PD-1 expression in primary CLL cells ex vivo, an effect that can be blocked by Bruton’s tyrosine kinase inhibition (BTKi). Importantly, profound reductions in circulating PD-1+ CLL cells were observed in patients within 1 month of initiating BTKi therapy and detection of high percentages of circulating PD-1+ CLL cells in patients treated with BTKi preceded the clinical diagnosis of disease progression. These findings suggest that PD-1 expression in circulating CLL cells may predict response and resistance to BTKi therapy.