Emerging role of BCR signaling inhibitors in immunomodulation of chronic lymphocytic leukemia

Abstract

Approved therapies that target the B-cell receptor (BCR) signaling pathway, such as ibrutinib and idelalisib, are known to show activity in chronic lymphocytic leukemia (CLL) via their direct effects on crucial survival pathways in malignant B cells. However, these therapies also have effects on T cells in CLL bymediating toxicity and possibly controlling disease. By focusing on the effects of BCR signaling inhibitors on the T-cell compartment, we may gain new insights into the comprehensivebiological outcomes of systemic treatment tofurtherunderstandmechanisms of drug efficacy, predict the toxicity or adverse events, and identify novel combinatorial therapies.Here,we reviewT-cellabnormalities in preclinicalmodels andpatient samples,finding that CLL T cells orchestrate immune dysfunction and immune-related complications. We then continue to address the effects of clinically available small molecule BCR signaling inhibitors on the immune cells, especially T cells, in the context of concomitant immune-mediated adverse events and implications for future treatment strategies. Our review suggests potentially novel mechanisms of action related to BCR inhibitors, providing a rationale to extend their use to other cancers and autoimmune disorders.