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

De Re De Re,Mascarin Mascarin,Repetto Repetto,Mussolin Mussolin,Caggiari Caggiari

doi:10.3390/jcm8101596

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.

Highlights

Hodgkin’s lymphoma (HL) is a largely curable malignancy of the lymphatic system
In addition to a link with programmed cell death 1 (PD-1), PD-L1 was found to interact with the CD80 co-stimulator T-cell receptor, resulting in the disruption of the PD-L1/PD-1 binding on mature primary dendritic cells, in the restriction of PD-1-positive T-cell function, and in a exacerbation of autoimmunity [12]. These findings revealed the potential of CD80 to increase T-cell activation trough CD28 costimulation, and by reducing the PD-1-driven coinhibitory signal (Figure 2)
A defective function of the PD-1/PD-L1 interaction in antigen presentation and/or effector T-cell functions arise as relevant for the immune checkpoint inhibitory response in classic HL (cHL), including the involvement of the secreted forms of PD-1 and PD-L1 [7,52]. These studies underline the important role of inflammation in the HL tumor microenvironment in the response(s) to therapy, which includes the CD28 expression on TILs, the CD80/CD86 level, the PD-L2 expression, and the stage of JAK/STAT signaling in HRS, among others

Summary

Hodgkin’s Lymphoma

Hodgkin’s lymphoma (HL) is a largely curable malignancy of the lymphatic system. Patients usually present with painless lymphadenopathy, a variety of systemic and organ-specific symptoms may exist. A defective function of the PD-1/PD-L1 interaction in antigen presentation and/or effector T-cell functions arise as relevant for the immune checkpoint inhibitory response in cHL, including the involvement of the secreted forms of PD-1 and PD-L1 [7,52] These studies underline the important role of inflammation in the HL tumor microenvironment in the response(s) to therapy, which includes the CD28 expression on TILs, the CD80/CD86 level, the PD-L2 expression, and the stage of JAK/STAT signaling in HRS, among others. The focus of several research topics is represented by TMB-estimating algorithms in a cancer-specific manner and the decrease in cost and time required for the TMB assessment

Adverse Effects

Angiogenesis and Extracellular Vesicles

Microbiome

Findings

Duration of Therapy and Future Directions in the Use of Checkpoint Inhibitors