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

  • Translational Research and Biomarkers
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Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

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.

Results

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.

Conclusions

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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Acknowledgement

The authors thank James P. Mahaffey, PhD, from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.

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Author notes

  1. Drs. Taichi Matsubara and Kazuki Takada contributed equally to this work.

Authors and Affiliations

  1. Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Taichi Matsubara MD, Kazuki Takada MD, PhD, Shinkichi Takamori MD, PhD, Akira Haro MD, PhD, Atsushi Osoegawa MD, PhD, Tetsuzo Tagawa MD, PhD & Yoshihiko Maehara MD, PhD

  2. Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Fukuoka, Japan

    Koichi Azuma MD, PhD & Tomoaki Hoshino MD, PhD

  3. Department of Thoracic Surgery, Clinical Research Institute, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan

    Gouji Toyokawa MD, PhD

  4. Department of Diagnostic Pathology, Kurume University School of Medicine, Fukuoka, Japan

    Akihiko Kawahara PhD & Jun Akiba PhD

  5. Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Isamu Okamoto MD, PhD & Yoichi Nakanishi MD, PhD

  6. Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Yoshinao Oda MD, PhD

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Correspondence to Kazuki Takada MD, PhD.

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10434_2019_7257_MOESM6_ESM.tif

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.

10434_2019_7257_MOESM7_ESM.tif

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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Matsubara, T., Takada, K., Azuma, K. et al. A Clinicopathological and Prognostic Analysis of PD-L2 Expression in Surgically Resected Primary Lung Squamous Cell Carcinoma. Ann Surg Oncol 26, 1925–1933 (2019). https://doi.org/10.1245/s10434-019-07257-3

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