Yu Kuan, Cao Yifan, Zhang Zihao, Wang Leihao, Gu Yichao, Xu Tianwei, Zhang Xiaolei, Guo Xinxin, Shen Zhenbin, Qin Jing
Department of General Surgery, Zhongshan Hospital Fudan University, Shanghai, China.
Gastric Cancer Center, Zhongshan Hospital Fudan University, Shanghai, China.
J Immunother Cancer. 2025 May 22;13(5):e011080. doi: 10.1136/jitc-2024-011080.
Gastric cancer (GC) remains a major global health burden. Despite the advancements in immunotherapy for patients with GC, the heterogeneity of GC limits response rates, especially in immune "cold" subtypes, including genomically stable and epithelial-mesenchymal transition GC. Common lymphatic endothelial and vascular endothelial receptor-1 (CLEVER-1), a newly recognized immune checkpoint molecule predominantly expressed on tumor-associated macrophages (TAMs), remains poorly understood in GC. This study aims to explore the clinical significance of CLEVER-1TAM infiltration, elucidate its role in modulating the tumor immune landscape, and investigate the therapeutic potential of CLEVER-1 blockade in enhancing immunotherapy.
This study analyzed two independent GC cohorts and single-cell RNA sequencing data (GSE183904). CLEVER-1 expression in TAMs was assessed via multiplex immunofluorescence, flow cytometry, and RNA sequencing. The clinical relevance of CLEVER-1TAM infiltration was evaluated in relation to tumor, node, metastases staging, molecular subtypes, prognosis, and immunochemotherapy response. Transcriptomic and pathway analyses characterized the immunophenotype of CLEVER-1TAMs. Functional assays examined their suppression on CD8T cells, while interventional experiments assessed the impact of CLEVER-1 blockade alone or with programmed cell death protein-1 (PD-1) inhibition.
CLEVER-1 was predominantly expressed on TAMs in GC and was associated with worse clinical outcomes. Transcriptomic and phenotypic analyses revealed that CLEVER-1TAMs display a dynamic immunophenotype and critically suppress T-cell function, fostering an immunosuppressive microenvironment. High CLEVER-1TAM infiltration was linked to poor response or adaptive resistance to PD-1 blockade therapy. CLEVER-1 blockade reprogrammed TAMs toward a pro-inflammatory phenotype, resulting in enhanced CD8T cell cytotoxicity and proliferation. Co-targeting CLEVER-1 and PD-1 synergistically enhanced antitumor responses.
High infiltration of CLEVER-1TAMs indicates immune suppression and poor prognosis in GC. The combination of CLEVER-1 and PD-1 blockade emerges as a dual-pronged strategy to boost immune-mediated tumor control and prevent treatment relapse in GC.
胃癌（GC）仍然是全球主要的健康负担。尽管胃癌患者的免疫治疗取得了进展，但胃癌的异质性限制了缓解率，尤其是在免疫“冷”亚型中，包括基因组稳定型和上皮-间质转化型胃癌。常见淋巴管内皮和血管内皮受体-1（CLEVER-1）是一种新发现的免疫检查点分子，主要表达于肿瘤相关巨噬细胞（TAM），在胃癌中的作用仍知之甚少。本研究旨在探讨CLEVER-1⁺ TAM浸润的临床意义，阐明其在调节肿瘤免疫格局中的作用，并研究CLEVER-1阻断在增强免疫治疗方面的治疗潜力。
本研究分析了两个独立的胃癌队列和单细胞RNA测序数据（GSE183904）。通过多重免疫荧光、流式细胞术和RNA测序评估TAM中CLEVER-1的表达。评估CLEVER-1⁺ TAM浸润与肿瘤、淋巴结、转移分期、分子亚型、预后和免疫化疗反应的临床相关性。转录组学和通路分析确定了CLEVER-1⁺ TAM的免疫表型。功能试验检测它们对CD8⁺ T细胞的抑制作用，而干预实验评估单独阻断CLEVER-1或联合程序性细胞死亡蛋白-1（PD-1）抑制的影响。
CLEVER-1主要在胃癌的TAM上表达，与较差的临床结果相关。转录组学和表型分析表明，CLEVER-1⁺ TAM表现出动态免疫表型，并严重抑制T细胞功能，促进免疫抑制微环境的形成。高CLEVER-1⁺ TAM浸润与对PD-1阻断治疗的低反应或适应性耐药相关。阻断CLEVER-1可使TAM重编程为促炎表型，导致CD8⁺ T细胞细胞毒性和增殖增强。联合靶向CLEVER-1和PD-1可协同增强抗肿瘤反应。
CLEVER-1⁺ TAM的高浸润表明胃癌存在免疫抑制和预后不良。联合阻断CLEVER-1和PD-1有望成为一种双管齐下的策略，以增强免疫介导的肿瘤控制并防止胃癌治疗复发。
