State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Guangdong Esophageal Cancer Institute, Guangzhou, China.
Department of Anesthesiology, Sun Yat-sen University Cancer Center, Guangzhou, China.
JAMA Netw Open. 2023 Jan 3;6(1):e2250965. doi: 10.1001/jamanetworkopen.2022.50965.
Sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) is a novel immune checkpoint molecule that is highly homologous to programmed cell death ligand 1 (PD-L1), but information remains limited about its role in esophageal squamous cell carcinoma (ESCC).
To explore the expression pattern and association of Siglec-15 with outcomes among patients with ESCC who received neoadjuvant chemoradiotherapy (CRT).
DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study was conducted at an academic institution in China. Participants included patients with ESCC who underwent neoadjuvant CRT and esophagectomy between June 2002 and December 2018. Multiplexed immunofluorescence staining was used to evaluate the expression of Siglec-15 and PD-L1 in tumor cells (TCs) or tumor-associated macrophages based on pre-CRT biopsies. Different immune phenotypes have been proposed and further validated in an independent cohort. Data analysis was conducted from January to May 2021.
Siglec-15 or PD-L1 positivity vs negativity.
Pathologic complete response (pCR), overall survival (OS), and recurrence-free survival (RFS).
Of 130 participants (median [range] age, 56 [42-73] years; 108 [83.1%] male participants) in the primary cohort, 58 patients (44.6%) achieved a pCR after neoadjuvant CRT. Siglec-15 and PD-L1 were detected in both TCs and macrophages. The percentage of Siglec-15-positive macrophages was notably higher than that of Siglec-15-positive TCs (median [IQR]: 34.4% [12.7%-64.3%] vs 4.8% [0.7%-25.6%]; P < .001). TC-Siglec-15 expression was significantly and positively associated with macrophage-Siglec-15 expression (r = 0.78; P < .001). Siglec-15 positivity was significantly associated with a higher rate of pCR (37 of 70 [52.9%] vs 21 of 60 [35.0%]; P = .04), more favorable OS (hazard ratio [HR], 0.46; 95% CI, 0.25-0.85; P = .01), and RFS (HR, 0.48; 95% CI, 0.26-0.88; P = .02). However, PD-L1 positivity in TCs was negatively associated with survival. Stratification analysis further revealed that patients with combined Siglec-15 positivity and PD-L1 negativity had better survival than those with other phenotypes. Major findings were reproducible in a validation cohort with 55 patients.
In this cohort study of patients with ESCC receiving neoadjuvant CRT, Siglec-15 positivity was associated with a better pathological response and more favorable survival. Siglec-15 could serve as a novel biomarker to identify potential candidates that may benefit from immunotherapy combined with CRT.
唾液酸结合免疫球蛋白样凝集素 15（Siglec-15）是一种新型免疫检查点分子，与程序性细胞死亡配体 1（PD-L1）高度同源，但关于其在食管鳞状细胞癌（ESCC）中的作用，信息仍然有限。
探讨 Siglec-15 的表达模式及其与接受新辅助放化疗（CRT）的 ESCC 患者结局的相关性。
设计、地点和参与者：这是一项在中国一所学术机构进行的回顾性队列研究。参与者包括 2002 年 6 月至 2018 年 12 月期间接受新辅助 CRT 和食管切除术的 ESCC 患者。基于术前活检，使用多重免疫荧光染色来评估 Siglec-15 和 PD-L1 在肿瘤细胞（TCs）或肿瘤相关巨噬细胞中的表达。在一个独立的队列中提出并进一步验证了不同的免疫表型。数据分析于 2021 年 1 月至 5 月进行。
Siglec-15 或 PD-L1 阳性与阴性。
病理完全缓解（pCR）、总生存期（OS）和无复发生存期（RFS）。
在主要队列的 130 名参与者（中位[范围]年龄，56[42-73]岁；108[83.1%]男性参与者）中，58 名患者（44.6%）在新辅助 CRT 后获得了 pCR。Siglec-15 和 PD-L1 均可在 TCs 和巨噬细胞中检测到。Siglec-15 阳性巨噬细胞的比例明显高于 Siglec-15 阳性 TCs（中位数[IQR]：34.4%[12.7%-64.3%]比 4.8%[0.7%-25.6%]；P < .001）。TC-Siglec-15 表达与巨噬细胞-Siglec-15 表达显著正相关（r = 0.78；P < .001）。Siglec-15 阳性与更高的 pCR 率显著相关（70 例中有 37 例[52.9%]比 60 例中有 21 例[35.0%]；P = .04）、更有利的 OS（风险比[HR]，0.46；95%置信区间，0.25-0.85；P = .01）和 RFS（HR，0.48；95%置信区间，0.26-0.88；P = .02）。然而，TCs 中 PD-L1 阳性与生存呈负相关。分层分析进一步显示，与其他表型相比，同时具有 Siglec-15 阳性和 PD-L1 阴性的患者具有更好的生存。在一个包含 55 名患者的验证队列中，主要发现具有可重复性。
在这项接受新辅助 CRT 的 ESCC 患者队列研究中，Siglec-15 阳性与更好的病理反应和更有利的生存相关。Siglec-15 可作为一种新的生物标志物，以识别可能从 CRT 联合免疫治疗中获益的潜在候选者。
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