Immune checkpoint blockade: the role of PD-1-PD-L axis in lymphoid malignancies

Abstract

The co-inhibitory receptor programmed cell death (PD)-1, expressed by immune effector cells, is credited with a protective role for normal tissue during immune responses, by limiting the extent of effector activation. Its presently known ligands, programmed death ligands (PD-Ls) 1 and 2, are expressed by a variety of cells including cancer cells, suggesting a role for these molecules as an immune evasion mechanism. Blocking of the PD-1-PD-L signaling axis has recently been shown to be effective and was clinically approved in relapsed/refractory tumors such as malignant melanoma and lung cancer, but also classical Hodgkin's lymphoma. A plethora of trials exploring PD-1 blockade in cancer are ongoing. Here, we review the role of PD-1 signaling in lymphoid malignancies, and the latest results of trials investigating PD-1 or PD-L1 blocking agents in this group of diseases. Early phase studies proved very promising, leading to the clinical approval of a PD-1 blocking agent in Hodgkin's lymphoma, and Phase III clinical studies are either planned or ongoing in most lymphoid malignancies.

Keywords: b7 antigens; chronic lymphocytic leukemia; hematological cancer; immune checkpoint blockade; lymphoma; programmed cell death 1.

Figure 1

PD-1- PD-L1 axis blockade in cancer. Notes: Signaling through PD-1 induces T cell anergy, with the physiological role of protecting from autoimmune damage. This mechanism is exploited by tumor cells expressing PD-1 ligands to escape immunity by suppressing host antitumor T cell responses (left). PD-1 or PD-L1 blocking antibodies have the capability to restore cytotoxic T cell functions including IFN-y and perforin production, which can lead to impressive antitumor responses (right). Abbreviations: PD, programmed cell death; PD-L1, programmed cell death receptor ligand-1.