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27.02.2019 | Translational Research and Biomarkers

A Clinicopathological and Prognostic Analysis of PD-L2 Expression in Surgically Resected Primary Lung Squamous Cell Carcinoma

Annals of Surgical Oncology
MD Taichi Matsubara, MD, PhD Kazuki Takada, MD, PhD Koichi Azuma, MD, PhD Shinkichi Takamori, MD, PhD Gouji Toyokawa, MD, PhD Akira Haro, MD, PhD Atsushi Osoegawa, MD, PhD Tetsuzo Tagawa, PhD Akihiko Kawahara, PhD Jun Akiba, MD, PhD Isamu Okamoto, MD, PhD Yoichi Nakanishi, MD, PhD Yoshinao Oda, MD, PhD Tomoaki Hoshino, MD, PhD Yoshihiko Maehara
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1245/​s10434-019-07257-3) contains supplementary material, which is available to authorized users.
Drs. Taichi Matsubara and Kazuki Takada contributed equally to this work.

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Immunotherapy targeting programmed cell death-1 (PD-1) and programmed death-ligand 1 (PD-L1) has shown dramatic therapeutic effects for lung squamous cell carcinoma (SCC), and PD-L1 expression has been shown not only to be a predictive biomarker for response to immunotherapy but also a prognostic factor for lung SCC. However, the clinical significance of programmed death-ligand 2 (PD-L2), another PD-1 ligand, remains unclear. Therefore, we analyzed PD-L2 expression by immunohistochemistry in surgically resected primary lung SCC.

Patients and Methods

PD-L1 and PD-L2 expression on tumor cells were analyzed in 211 primary lung SCC specimens by immunohistochemistry. Additionally, numbers of CD3+, CD4+, and CD8+ tumor-infiltrating lymphocytes were also examined.


The rates of positive PD-L2 expression were 77.3% and 67.3% using 5% and 10% cut-off values, respectively. Low PD-L2 expression on tumor cells was statistically associated with histological type (non-keratinizing/keratinizing) and lymphatic invasion. PD-L2-positive patients had significantly longer postoperative survival time (log-rank test; p = 0.0170 at 5% cut-off and p = 0.0500 at 10% cut-off). Furthermore, survival analysis according to PD-L1 and PD-L2 expression revealed that PD-L1-positive and PD-L2-negative patients had the most unfavorable prognosis.


PD-L2 protein expression was associated with prognosis in primary lung SCC patients. PD-L2 expression might be a potential biomarker for response to PD-1/PD-L1-targeted immunotherapy, which should be investigated in future studies.

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Supplementary material 1 (DOCX 19 kb)
Supplementary material 2 (DOCX 22 kb)
Supplementary material 3 (DOCX 25 kb)
Supplementary material 4 (DOCX 23 kb)
Supplementary material 5 (DOCX 24 kb)
Supplementary material 6 (TIFF 9525 kb). Supplementary Figure 1 A receiver operating characteristic curve in the analysis of enrolled patients. 5 year-survival was used as the state variable.
Supplementary material 7 (TIFF 18325 kb). Supplementary Figure 2. Representative images of PD-L1, PD-L2, CD3, CD4, and CD8 expression in lung squamous cell carcinoma specimens. Negative (A) and positive (B) PD-L1 staining, and negative (C) and positive (D) PD-L2 staining, which were detected on the membrane of tumor cells. Low (E, G, I) and high (F, H, J) numbers of CD3- (E, F), CD4- (G, H), and CD8-positive (I, J) tumor infiltrating lymphocytes. PD-L1, programmed death-ligand 1; PD-L2, programmed death-ligand 2; CD3, cluster of differentiation 3; CD4, cluster of differentiation 4; CD8, cluster of differentiation 8. Scale bar: 100 μm.
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