CLDN18.2 的表达及其对胃癌预后和免疫微环境的影响。
CLDN18.2 expression and its impact on prognosis and the immune microenvironment in gastric cancer.
机构信息
Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, China.
The First Clinical Medical College of Zunyi Medical University, Zunyi, 563006, Guizhou, China.
出版信息
BMC Gastroenterol. 2023 Aug 16;23(1):283. doi: 10.1186/s12876-023-02924-y.
BACKGROUND
The investigational use of zolbetuximab (IMAB362), a groundbreaking monoclonal antibody medication targeting claudin 18.2 (CLDN18.2), for treatment of advanced gastrointestinal cancers is currently underway. The unclear clinicopathological characteristics and tumour immune microenvironment of CLDN18.2-positive gastric cancer (GC) make it difficult to develop and optimize CLDN18.2-targeted therapies.
METHODS
A total of 451 tumour tissues, 342 matched paraneoplastic tissues, and 107 matched metastatic lymph nodes were collected from GC patients. These specimens were stained for CLDN18.2 expression and quantified using immunohistochemistry (IHC). Correlations between CLDN18.2 expression and clinicopathological features as well as immune-related factors were analysed. Survival curves were drawn using the Kaplan‒Meier approach, and independent factors affecting GC prognosis were identified using Cox regression analysis. Information from relevant databases was used for corroboration.
RESULTS
Expression of the CLDN18.2 gene was significantly lower in gastric tumour tissues than in normal tissues (p < 0.001) but comparable in metastatic lymph nodes (p = 0.851). CLDN18.2 expression was significantly associated with Borrmann type, degree of differentiation, PD-L1 expression, and survival in GC patients and was identified as an independent risk factor for patient prognosis (HR = 1.57, 95% CI 1.16-2.11, p = 0.003). There was no correlation between CLDN18.2 expression and HER2, Lauren type, tumour size, TNM stage, or any other clinicopathological characteristic. In CLDN18.2-positive tumours, fractions of CD4 + T cells and CD8 + T cells were significantly higher than those in CLDN18.2-negative tumours. Patients with CLDN18.2-negative expression and significant CD4 + T-cell or CD8 + T-cell infiltration had the best prognosis (5-year OS: 61.0%, P = 0.036; 5-year OS: 62.2%, P = 0.034).
CONCLUSIONS
CLDN18.2 is expressed at a low level in tumour tissues and serves as an independent prognostic factor for patients with GC. Furthermore, CLDN18.2 correlates with immune infiltrating cells and PD-L1 expression.
背景
研究性使用靶向 Claudin18.2（CLDN18.2）的新型单克隆抗体药物唑来膦单抗（zolbetuximab，IMAB362）治疗晚期胃肠癌正在进行中。CLDN18.2 阳性胃癌（GC）的临床病理特征和肿瘤免疫微环境不明确，使得 CLDN18.2 靶向治疗的开发和优化变得困难。
方法
从 GC 患者中收集了 451 例肿瘤组织、342 例配对癌旁组织和 107 例配对转移淋巴结。使用免疫组织化学（IHC）对 CLDN18.2 表达进行染色和定量。分析 CLDN18.2 表达与临床病理特征和免疫相关因素的相关性。使用 Kaplan-Meier 方法绘制生存曲线，使用 Cox 回归分析确定影响 GC 预后的独立因素。使用相关数据库的信息进行佐证。
结果
CLDN18.2 基因在胃癌组织中的表达明显低于正常组织（p<0.001），但在转移淋巴结中无差异（p=0.851）。CLDN18.2 表达与 Borrmann 型、分化程度、PD-L1 表达和 GC 患者的生存显著相关，并被确定为患者预后的独立危险因素（HR=1.57，95%CI 1.16-2.11，p=0.003）。CLDN18.2 表达与 HER2、Lauren 型、肿瘤大小、TNM 分期或任何其他临床病理特征均无相关性。在 CLDN18.2 阳性肿瘤中，CD4+T 细胞和 CD8+T 细胞的比例明显高于 CLDN18.2 阴性肿瘤。CLDN18.2 表达阴性且 CD4+T 细胞或 CD8+T 细胞浸润显著的患者预后最佳（5 年 OS：61.0%，P=0.036；5 年 OS：62.2%，P=0.034）。
结论
CLDN18.2 在肿瘤组织中低表达，是 GC 患者的独立预后因素。此外，CLDN18.2 与免疫浸润细胞和 PD-L1 表达相关。
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