PD-L2 Expression in Human Tumors: Relevance to Anti-PD-1 Therapy in Cancer

Abstract

Tumor-associated PD-L1 expression is predictive of clinical response to PD-1-directed immunotherapy. However, PD-L1-negative patients may also respond to PD-1 checkpoint blockade, suggesting that other PD-1 ligands may be relevant to the clinical activity of these therapies. The prevalence of PD-L2, the other known ligand of PD-1, and its relationship to response to anti-PD-1 therapy were evaluated. PD-L2 expression was assessed in archival tumor tissue from seven indications using a novel immunohistochemical assay. In addition, relationships between clinical response and PD-L2 status were evaluated in tumor tissues from patients with head and neck squamous cell carcinoma (HNSCC) with recurrent or metastatic disease, treated with pembrolizumab. PD-L2 expression was observed in all tumor types and present in stromal, tumor, and endothelial cells. The prevalence and distribution of PD-L2 correlated significantly with PD-L1 ( = 0.0012-<0.0001); however, PD-L2 was detected in the absence of PD-L1 in some tumor types. Both PD-L1 and PD-L2 positivity significantly predicted clinical response to pembrolizumab on combined tumor, stromal and immune cells, with PD-L2 predictive independent of PD-L1. Response was greater in patients positive for both PD-L1 and PD-L2 (27.5%) than those positive only for PD-L1 (11.4%). PD-L2 status was also a significant predictor of progression-free survival (PFS) with pembrolizumab independent of PD-L1 status. Longer median times for PFS and overall survival were observed for PD-L2-positive than PD-L2-negative patients. Clinical response to pembrolizumab in patients with HNSCC may be related partly to blockade of PD-1/PD-L2 interactions. Therapy targeting both PD-1 ligands may provide clinical benefit in these patients. .

Development of a Companion Diagnostic for Pembrolizumab in Non–Small Cell Lung Cancer Using Immunohistochemistry for Programmed Death Ligand-1

“…The purported sequence of events is as follows: neoplastic growth immune response adaptive PD-L1 expression (triggered by release of cytokines, most notably interferon-c) attenuation of immune response (mediated by the PD-1 receptor). One variation on this theme is that some tumors may effect immune modulation through expression of PD-L2 26 in the absence of concomitant PD-L1 expression; the presence of different molecular alterations could also potentially impact response to specific therapies, representing other possible explanations for pembrolizumab efficacy in tumors with TPS lower than 50%.…”

PD-L1 expression in non-small cell lung cancer: Correlations with genetic alterations

“…Currently, PD-L1 IHC has the highest evidence as predictive biomarker for PD-1 directed therapy. 21 Another potential biomarker of interest is the second PD-1 ligand PD-L2, 22 while the PD-1 receptor itself has less predictive value. 23 Besides the analysis of checkpoint proteins, genomic techniques to evaluate the mutational burden and neoantigens are rapidly evolving and might have superior predictive value for anti-PD-1 as well as for anti-CTLA4 therapy.…”

Cancer immunotherapy: a brief review of the history, possibilities, and challenges ahead

“…While B7 ligands are expressed by professional APCs (includes dendritic cells, macrophages and B cells), PD-L1 can be expressed on many cell types, including T-cells, epithelial cells, endothelial cells, and tumor cells after exposure to interferon-gamma, produced later in the immune response by activated T cells. PD-L2 is primarily expressed on dendritic cells and monocytes, but can be induced in a wide variety of other immune cells and nonimmune cells [68] .…”