Tissue and circulating PD-L2: moving from health and immune-mediated diseases to head and neck oncology

Amongst the chief targets of immune-checkpoint inhibitors (ICIs), namely the Programmed cell death protein 1 (PD-1)/PD-Ligands (Ls) axis, most research has focused on PD-L1, while to date PD-L2 is still under-investigated. However, emerging data support PD-L2 relevant expression in malignancies of the head and neck area, mostly in head and neck squamous cell carcinoma (HNSCC) and salivary gland cancers (SGCs). In this context, ICIs have achieved highly heterogeneous outcomes, emphasizing an urgent need for the identification of predictive biomarkers. With the present review, we aimed at describing PD-L2 biological significance by focusing on its tissue expression, its binding to PD-1 and RGMb receptors, and its impact on physiological and anti-cancer immune response. Specifically, we reported PD-L2 expression rates and significant clinical correlates among different head and neck cancer histotypes. Finally, we described the biology of soluble PD-L2 form and its potential application as a prognostic and/or predictive circulating biomarker. [Display omitted] •Immune-checkpoint inhibitors achieved variable results in head and neck malignancies.•Except for PD-L1 in HNSCC, few validated predictive markers are available.•Research concerning PD-1/PDLs axis has neglected PD-L2.•Head and neck cancer expresses PD-L2, correlating with clinical/prognostic outcomes.•Soluble PD-L2 is a promising, minimally invasive liquid biopsy biomarker.