PD-L2 is associated with progression-free survival (PFS) among patients with head and neck squamous cell carcinoma (HNSCC) treated with pembrolizumab and could be another immune checkpoint target, according to a study published in Clinical Cancer Research.1

The study evaluated the expression of PD-L2 of archival samples from 7 different tumor types by immunohistochemistry using a novel anti-PD-L2 antibody. A pathologist scored the resulting staining. The cellular distribution of PD-L2 was assessed by in situ hybridization.

PD-L2 was expressed by all 7 tumor types by stromal, tumor, and endothelial cells. PD-L1 staining was associated with PD-L2 staining (P = .0012 to < .0001), but PD-L2 was also expressed by tumors without PD-L1 expression.

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The study also evaluated 172 tumor samples from the KEYNOTE-12 trial (ClinicalTrials.gov Identifier: NCT01848834) of patients with HNSCC positive or unselected for PD-L1 expression for PD-L2 expression levels. Positive expression was defined as at least 1% of cells stained.

Clinical response to pembrolizumab was significantly associated with PD-L1 and PD-L2 expression. Patients negative for PD-L1 expression demonstrated a 5% (95% CI, 0.1-24.9%) response rate compared with 23% (95% CI, 16-31.4%) and 26.6% (95% CI, 18-36.7%) for patients who expressed PD-L1 or PD-L2, respectively.

Expression of both PD-L1 and PD-L2 increased the response to 27.5% (95% CI, 18.6-37.8) compared with either ligand expressed alone, at 11.4% (95% CI, 3.2-26.7) for PD-L1-positive/PD-L2-negative and 0% (95% CI, 0-70.8%) for PD-L1-negative/PD-L2-negative.

PD-L2 expression was also significantly associated with PFS (P = .005), even after adjustment for PD-L1 expression (P = .013). The median PFS among patients with PD-L2 expression was 65 days compared with 59 days among those without PD-L2 expression.

Overall survival (OS) was also associated with PD-L2 expression (P = .030), but not after adjustment for PD-L1 expression (P = .112).

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The median OS was 303 days among PD-L2-positive patients compared with 199 among those who were PD-L2-negative.

According to the authors, these data suggest that “PD-L2 expression may provide information beyond that of PD-L1 in predicting clinical response to anti-PD-1 targeted agents…and may help in identifying those patients who may derive benefit from these therapies.”


  1. Yearley JH, Gibson C, Yu N, et al. PD-L2 expression in human tumors: relevance to anti-PD-1 therapy in cancer. Clin Cancer Res. 2017 Jun 16. doi: 10.1158/1078-0432.CCR-16-1761 [Epub ahead of print]