Cozac-Szőke Andreea-Raluca, Tinca Andreea Cătălina, Negovan Anca, Vilaia Alexandra, Cozac Dan-Alexandru, Cocuz Iuliu-Gabriel, Sabău Adrian Horațiu, Hagău Raluca-Diana, Chiorean Diana-Maria, Lazar Andreea-Bianca, Turdean Sabin, Szász Emőke-Andrea, Tomuț Alexandru Nicușor, Cotoi Ovidiu Simion
Doctoral School of Medicine and Pharmacy, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, 540142 Targu Mures, Romania.
Pathophysiology Department, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, 540142 Targu Mures, Romania.
Int J Mol Sci. 2025 Sep 5;26(17):8637. doi: 10.3390/ijms26178637.
Gastric cancer remains a major global health burden, with limited response rates to current immunotherapies targeting the programmed death-ligand 1 (PD-1/PD-L1) axis. Recent studies have identified sialic acid-binding immunoglobulin-like lectin 15 (SIGLEC-15) as a novel immune checkpoint molecule that may drive immune evasion through PD-L1-independent pathways. This study aimed to evaluate the expression patterns of SIGLEC-15 and PD-L1 in gastric adenocarcinoma and to investigate their associations with clinicopathological features and patient outcomes. We retrospectively analyzed 133 consecutive cases of gastric adenocarcinoma with complete clinicopathologic and follow-up data. Immunohistochemical staining was performed on formalin-fixed tumor samples; SIGLEC-15 expression on tumor cells was quantified by H-score (high expression defined as ≥110) and PD-L1 status by combined positive score (CPS, positive if ≥1). High SIGLEC-15 expression correlated with multiple adverse pathological features, including lymphatic ( = 0.003), venous ( = 0.030), and perineural invasion ( = 0.010), and was associated with significantly poorer 3-year overall survival (hazard ratio = 3.36, < 0.001). While SIGLEC-15 and PD-L1 expression were not mutually exclusive, an inverse relationship was generally observed. Patients with dual positivity (SIGLEC-15 high/PD-L1 CPS ≥ 1) showed the lowest 36-month survival (32%), compared to 56% in the dual-negative group (SIGLEC-15 low/PD-L1 CPS < 1). These results highlight the clinical relevance of SIGLEC-15 as an independent marker of tumor aggressiveness and poor prognosis in gastric adenocarcinoma. Moreover, stratification based on combined SIGLEC-15 and PD-L1 CPS expression revealed that patients co-expressing high levels of both markers experienced the poorest survival outcomes. These findings suggest that the dual assessment of SIGLEC-15 and PD-L1 may enhance prognostic accuracy and support immunotherapeutic decision-making in gastric cancer.
胃癌仍然是一个重大的全球健康负担，目前针对程序性死亡配体1（PD-1/PD-L1）轴的免疫疗法的反应率有限。最近的研究已将唾液酸结合免疫球蛋白样凝集素15（SIGLEC-15）确定为一种新型免疫检查点分子，它可能通过不依赖PD-L1的途径驱动免疫逃逸。本研究旨在评估SIGLEC-15和PD-L1在胃腺癌中的表达模式，并研究它们与临床病理特征及患者预后的关联。我们回顾性分析了133例具有完整临床病理和随访数据的连续性胃腺癌病例。对福尔马林固定的肿瘤样本进行免疫组织化学染色；通过H评分（高表达定义为≥110）对肿瘤细胞上的SIGLEC-15表达进行定量，并通过联合阳性评分（CPS，≥1为阳性）对PD-L1状态进行评估。SIGLEC-15高表达与多种不良病理特征相关，包括淋巴管浸润（P = 0.003）、静脉浸润（P = 0.030）和神经周围浸润（P = 0.010），并与3年总生存率显著较差相关（风险比 = 3.36，P < 0.001）。虽然SIGLEC-15和PD-L1表达并非相互排斥，但总体上观察到一种负相关关系。双阳性（SIGLEC-15高/PD-L1 CPS≥1）患者的36个月生存率最低（32%），而双阴性组（SIGLEC-15低/PD-L1 CPS < 1）为56%。这些结果突出了SIGLEC-15作为胃腺癌肿瘤侵袭性和不良预后独立标志物的临床相关性。此外，基于SIGLEC-15和PD-L1 CPS联合表达的分层显示，同时高表达这两种标志物的患者生存结局最差。这些发现表明，对SIGLEC-15和PD-L1进行双重评估可能会提高预后准确性，并为胃癌的免疫治疗决策提供支持。
