Classical Hodgkin's Lymphoma in the Era of Immune Checkpoint Inhibition

Abstract

: The ligation of programmed cell death 1 (PD-1) with programmed cell death ligand PD-L activates the immune checkpoint leading to T-cell dysfunction, exhaustion, and tolerance, especially in Hodgkin lymphoma (HL) where the PD-L/ Janus kinase (Jak) signaling was frequently found altered. Anti-PD-1 or anti-PD-L1 monoclonal antibodies can reverse this immune checkpoint, releasing the brake on T-cell responses. The characterization of the mechanisms regulating both the expression of PD-1 and PD-L and their function(s) in HL is ongoing. We provide in this review the recent findings focused on this aim with special attention on the major research topics, such as adverse events and resistance to PD-1-PD-L1 inhibitor treatment, together with a part about angiogenesis, extracellular vesicles, and microbiome in HL pathogenesis.

Keywords: EBV; Hodgkin lymphoma; PD-1; PD-L1; adverse events; angiogenesis; cytokines; extracellular vesicles; immune checkpoint inhibitors.

Figure 1

B-cells and Reed–Sternberg cells (HRS) express on their own membrane the CD40 receptor, which binds the CD40 ligand (CD40L) on activated helper T cells. The interaction activates a signal cascade leading to B-cell proliferation through nuclear kappa-light-chain-enhancer of activated B cells (NF-kB)-mediated effector functions. CD40/CD40L interaction also activated deaminase enzyme, responsible for the Ig class exchanges. The Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) is expressed in EBV latency II stage, which is a characteristic of Hodgkin lymphoma (HL). LMP1 acts as a dysregulated mimic of CD40, inducing enhanced cell activation and survival.

Figure 2

Programmed cell death 1 (PD-1) expression on T-cells (A) PD-1 expression is induced when the T-cell receptor (TCR) recognizes an antigen during differentiation from a naïve cell into an effector cell. In the absence of TCR signaling, PD-1 is lost, (B) PD-1 expression is maintained upon chronic antigen stimulation such as during chronic viral/bacterial infections and in cancer. When PD-1 binds the programmed cell death 1 ligand (PD-L1) it inhibits TCR/ Major Histocompatibility Complex (MHC) and CD80/CD28 signaling and therby inhibits T cell activation. PD-1–PD-L1 binding occurs predominantly in Hodgkin lymphoma (HL) due to frequent genetic alterations leading to up-regulation of PD-L1/PD-L2/ Janus kinase 2 (JAK 2) signaling or to expression of the Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) protein that induces the expression of PD-L1 in the Hodgkin Reed-Sternberg (HRS) cells. PD-L1 molecules can also bind the receptor CD80, thus attenuating the signaling from PD-1–PD-L1 interaction.

Figure 3

Interactions between the microbiome and Hodgkin Reed-Sternberg (HRS) cells and effects of the release of extracellular vesicles/exosomes into the Hodgkin lymphoma (HL microenvironment. Intestinal microbiota has been suggested to play a role in HL development by acting on the host immune system, for instance type 1 T helper cells (Th1). Exosomes and extracellular vesicles from HL and Epstein-Barr virus (EBV)-positive HL exacerbate the worst phenotype of the tumor by remodeling the tumor microenvironment trough the delivery of Vascular Epithelial Growth Factor (VEGF, which promotes micro-vessel density), Latent Membrane Protein 1 (LMP1, which activates various molecular pathways including B-cell survival), while Programmed Cell Death Ligand 1 (PD-L1) trough binding of the Programmed Cell Death 1 (PD-1) receptor induces immunosuppressive function of the T-cells.