(1) Yu K (2) Cao Y (3) Zhang Z (4) Wang L (5) Gu Y (6) Xu T (7) Zhang X (8) Guo X (9) Shen Z (10) Qin J
Yu, Cao, Zhang et al. showed that in the gastric cancer TME, Common Lymphatic Endothelial and Vascular Endothelial Receptor-1 (CLEVER-1) was primarily expressed on TAMs that increasingly polarized from a proinflammatory to an immunosuppressive profile as disease progressed. CLEVER-1+ TAM abundance was associated with fewer and exhausted tumor-infiltrating CD8+ T cells, poor prognosis, and weak response/resistance to anti-PD-1-based therapy. In cell cultures, CLEVER-1 blockade promoted a proinflammatory TAM phenotype and CD8+ T cell cytotoxicity/proliferation, and synergized with PD-1 blockade to enhance antitumor responses.
Contributed by Paula Hochman
(1) Yu K (2) Cao Y (3) Zhang Z (4) Wang L (5) Gu Y (6) Xu T (7) Zhang X (8) Guo X (9) Shen Z (10) Qin J
Yu, Cao, Zhang et al. showed that in the gastric cancer TME, Common Lymphatic Endothelial and Vascular Endothelial Receptor-1 (CLEVER-1) was primarily expressed on TAMs that increasingly polarized from a proinflammatory to an immunosuppressive profile as disease progressed. CLEVER-1+ TAM abundance was associated with fewer and exhausted tumor-infiltrating CD8+ T cells, poor prognosis, and weak response/resistance to anti-PD-1-based therapy. In cell cultures, CLEVER-1 blockade promoted a proinflammatory TAM phenotype and CD8+ T cell cytotoxicity/proliferation, and synergized with PD-1 blockade to enhance antitumor responses.
Contributed by Paula Hochman
BACKGROUND: 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-1(+)TAM infiltration, elucidate its role in modulating the tumor immune landscape, and investigate the therapeutic potential of CLEVER-1 blockade in enhancing immunotherapy. METHODS: 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-1(+)TAM 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-1(+)TAMs. Functional assays examined their suppression on CD8(+)T cells, while interventional experiments assessed the impact of CLEVER-1 blockade alone or with programmed cell death protein-1 (PD-1) inhibition. RESULTS: CLEVER-1 was predominantly expressed on TAMs in GC and was associated with worse clinical outcomes. Transcriptomic and phenotypic analyses revealed that CLEVER-1(+)TAMs display a dynamic immunophenotype and critically suppress T-cell function, fostering an immunosuppressive microenvironment. High CLEVER-1(+)TAM 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 CD8(+)T cell cytotoxicity and proliferation. Co-targeting CLEVER-1 and PD-1 synergistically enhanced antitumor responses. CONCLUSIONS: High infiltration of CLEVER-1(+)TAMs 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.
Author Info: (1) Department of General Surgery, Zhongshan Hospital Fudan University, Shanghai, China. Gastric Cancer Center, Zhongshan Hospital Fudan University, Shanghai, China. (2) Department
Author Info: (1) Department of General Surgery, Zhongshan Hospital Fudan University, Shanghai, China. Gastric Cancer Center, Zhongshan Hospital Fudan University, Shanghai, China. (2) Department of General Surgery, Zhongshan Hospital Fudan University, Shanghai, China. Gastric Cancer Center, Zhongshan Hospital Fudan University, Shanghai, China. (3) Department of General Surgery, Zhongshan Hospital Fudan University, Shanghai, China. Gastric Cancer Center, Zhongshan Hospital Fudan University, Shanghai, China. (4) Department of General Surgery, Zhongshan Hospital Fudan University, Shanghai, China. Gastric Cancer Center, Zhongshan Hospital Fudan University, Shanghai, China. (5) Department of General Surgery, Zhongshan Hospital Fudan University, Shanghai, China. Gastric Cancer Center, Zhongshan Hospital Fudan University, Shanghai, China. (6) Department of General Surgery, Zhongshan Hospital Fudan University, Shanghai, China. (7) Department of Pathology, Zhongshan Hospital Fudan University, Shanghai, China. (8) Department of Pathology, Zhongshan Hospital Fudan University, Shanghai, China. (9) Department of General Surgery, Zhongshan Hospital Fudan University, Shanghai, China qin.jing@zs-hospital.sh.cn shen.zhenbin@zs-hospital.sh.cn. Gastric Cancer Center, Zhongshan Hospital Fudan University, Shanghai, China. (10) Department of General Surgery, Zhongshan Hospital Fudan University, Shanghai, China qin.jing@zs-hospital.sh.cn shen.zhenbin@zs-hospital.sh.cn. Gastric Cancer Center, Zhongshan Hospital Fudan University, Shanghai, China.
Citation: J Immunother Cancer 2025 May 22 13: Epub05/22/2025
