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. 2025 Dec;11(1):2526993.
doi: 10.1080/20565623.2025.2526993. Epub 2025 Jul 2.

The expression and prognostic predictive value of PD-L2 in patients undergoing radical gastric cancer surgery

Xiuping Zhang  1   2 , Maodong Fu  2   3 , Zhiyong Li  1   2 , Feng Shen  1   2   4 , Huan Chen  2   5 , Zhiming Wang  1   2   4 , Jingmei Zheng  2   5
Affiliations

The expression and prognostic predictive value of PD-L2 in patients undergoing radical gastric cancer surgery

Xiuping Zhang et al. Future Sci OA. 2025 Dec.

Abstract

Background: The expression and prognostic predictive value of programmed death-ligand 2 (PD-L2) in patients undergoing radical gastric cancer (GC) surgery remains unclear.

Methods: PD-L2 expression in tumor cells (TC) and tumor-infiltrating immune cells (TIIC) was evaluated by immunohistochemistry. Kaplan-Meier and Cox models were used to evaluate the association of PD-L2 with disease-free survival (DFS) and overall survival (OS).

Results: This study included 299 patients and the average age was 63.76 ± 11.83 years, with 218 males (72.91%) and 81 females (27.09%). TC PD-L2 expression was significantly associated with poorer DFS (HR = 2.177, 95% CI 1.364-3.474, P = 0.001) and OS (HR = 1.943, 95% CI 1.191-3.169, P = 0.008). Multivariate analysis confirmed TC PD-L2 expression as an independent poor prognostic factor for DFS (HR = 2.121, 95% CI 1.325-3.393, P = 0.002) and OS (HR = 1.812, 95% CI 1.109-2.961, P = 0.018). PD-L2 in TIIC did not correlate with survival. Other poor prognostic factors included age ≥60, vascular invasion, advanced postoperative stage, and HER2 positivity.

Conclusions: PD-L2 expression in TC is an independent prognostic biomarker in GC, linked to poorer DFS and OS, suggesting its potential for identifying high-risk patients for personalized therapies.

Keywords: Gastric cancer; PD-L2; disease-free survival; immunohistochemistry; overall survival; prognosis.

Plain language summary

Gastric cancer (GC) is a serious condition where tumors form in the stomach. Despite surgery to remove tumors, many patients face the risk of the cancer returning. Researchers are working to find ways to predict which patients will have better or worse outcomes after surgery.This study focused on a protein called PD-L2, which helps tumors escape the immune system. While PD-L1, a similar protein, has been widely studied, PD-L2 has been less researched in GC. The researchers looked at PD-L2 levels in tumor cells and immune cells in 299 GC patients who had surgery. They found that when PD-L2 was present in the tumor cells, patients were more likely to have a shorter survival and higher chances of the cancer returning. However, PD-L2 in immune cells did not seem to affect survival.The study suggests that testing for PD-L2 in tumor cells could help doctors identify patients who are at higher risk and may need closer monitoring or different treatments after surgery.In summary, PD-L2 in tumor cells could help predict patient outcomes and guide better treatment decisions for GC patients.

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Conflict of interest statement

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Figures

Figure 1.
Figure 1.
Programmed death ligand 2 (PD-L2) immunohistochemical staining intensity scoring in tumor cells from radical gastrectomy specimens of gastric adenocarcinoma: A: No staining (0 points), B: Yellow staining (1 point), C: Brownish-yellow staining (2 points).
Figure 2.
Figure 2.
Flowchart of patient selection and analysis. From 385 GC patients, 86 were excluded, leaving 299 for analysis. PD-L2 expression was assessed using immunohistochemistry, categorizing patients into TC and TIIC PD-L2 positive/negative groups. Survival analyses examined PD-L2’s impact on disease-free survival (DFS) and overall survival (OS) in GC patients.
Figure 3.
Figure 3.
Kaplan-Meier survival curves comparing overall survival (OS) and disease-free survival (DFS) in patients based on PD-L2 expression. (A) OS for TC PD-L2 positive vs. negative, (B) DFS for TC PD-L2 positive vs. negative, (C) OS for TIIC PD-L2 positive vs. negative, (D) DFS for TIIC PD-L2 positive vs. negative.
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