Immune Checkpoint Inhibition in Hodgkin Lymphoma

Abstract

Intricate systems of checkpoints such as the programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) axis regulate adaptive immune responses to protect against tissue damage. However, diverse cancers can exploit these pathways to evade or suppress antitumor immunity, leading to tumor progression. Correspondingly, immune checkpoint inhibitors that block PD-1/PD-L1 signaling have shown marked therapeutic efficacy in certain cancers, such as Hodgkin lymphoma. Reed-Sternberg cells, the hallmark cells of Hodgkin lymphoma, commonly overexpress PD-1 ligands, and recent clinical trials have demonstrated impressive response rates with the PD-1 inhibitors nivolumab and pembrolizumab in relapsed or refractory Hodgkin lymphoma, leading to their FDA approval in this setting. Current efforts are underway to improve clinical responses by incorporating PD-1 inhibitors into earlier treatment regimens and identifying therapeutic agents that synergize with PD-1 inhibitors. This review summarizes our understanding of the PD-1/PD-L1 axis in Hodgkin lymphoma, recent clinical studies of anti-PD-1 monotherapy and promising combination immunotherapy in the pipeline.

Figure 1

PD-1 blockade in Hodgkin lymphoma. (A) PD-L1 and PD-L2 are upregulated in Hodgkin Reed-Sternberg (HRS) cells through several mechanisms, including amplification of chromosome 9p.24 which encodes the PDL1 and PDL2 loci. JAK2 is also encoded on chromosome 9p.24, and JAK-STAT signaling promotes PD-L1 and PD-L2 expression. In EBV-associated Hodgkin lymphoma, latent membrane protein 1 (LMP1) can promote PD-L1 and PD-L2 expression through AP-1. (B) T cells within the tumor microenvironment express PD-1, which recognizes PD-L1 and PD-L2 expressed on HRS cells, as well as other leukocytes such as macrophages. Antibodies such as nivolumab and pembrolizumab block PD-1 to disrupt PD-1/PD-L1 signaling.