Digestive Diseases Center, The Seventh Affiliated Hospital Sun Yat-sen University, Shenzhen, Guangdong, China.
Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China.
J Immunother Cancer. 2024 Oct 24;12(10):e009983. doi: 10.1136/jitc-2024-009983.
Tumor-associated macrophages (TAMs) have been demonstrated to be associated with tumor progression. However, the different subpopulations of TAMs and their roles in gastric cancer (GC) remain poorly understood. This study aims to assess the effects of Spi-1 proto-oncogene (SPI1)CD68 TAMs in GC.
The distribution of SPI1CD68 TAMs in GC tissue was estimated by immunohistochemistry, immunofluorescence, and flow cytometry. Single-cell transcriptome analysis and multiplex fluorescence immunohistochemistry were applied to explore the role of SPI1CD68 TAMs in an immune contexture. SPI1 overexpression or knockdown cells were constructed to evaluate its role in macrophage polarization and angiogenesis in vitro and in vivo. Chromatin immunoprecipitation was used to verify the mechanism of SPI1 transcriptional function. The effect of combined antiangiogenic and immunotherapy was further validated using mouse peritoneal metastasis models.
Single-cell transcriptome analysis and immunohistochemistry demonstrated that SPI1 was expressed in macrophages, with a higher enrichment in metastatic lesions than in primary tumors. Higher SPI1CD68 TAMs infiltration was associated with poor overall survival. Mechanically, SPI1 promoted the M2-type macrophage polarization. SPI1 could bind to the promoter of vascular endothelial growth factor A and facilitate angiogenesis. Moreover, the level of SPI1CD68 TAMs infiltration was closely related to the efficacy of immunotherapy, especially when combined with antiangiogenic therapy.
The present study showed that SPI1CD68 TAMs are a promising biomarker for predicting prognosis, antiangiogenic drug sensitivity, and combination target of immunotherapy in patients with GC.
肿瘤相关巨噬细胞（TAMs）已被证实与肿瘤进展有关。然而，TAMs 的不同亚群及其在胃癌（GC）中的作用仍知之甚少。本研究旨在评估 Spi-1 原癌基因（SPI1）CD68 TAMs 在 GC 中的作用。
通过免疫组织化学、免疫荧光和流式细胞术评估 SPI1CD68 TAMs 在 GC 组织中的分布。单细胞转录组分析和多重荧光免疫组化用于探索 SPI1CD68 TAMs 在免疫微环境中的作用。构建 SPI1 过表达或敲低细胞，以评估其在体外和体内巨噬细胞极化和血管生成中的作用。染色质免疫沉淀用于验证 SPI1 转录功能的机制。进一步使用小鼠腹膜转移模型验证联合抗血管生成和免疫治疗的效果。
单细胞转录组分析和免疫组织化学显示，SPI1 在巨噬细胞中表达，在转移性病变中的富集程度高于原发性肿瘤。较高的 SPI1CD68 TAMs 浸润与总生存期不良相关。机制上，SPI1 促进 M2 型巨噬细胞极化。SPI1 可与血管内皮生长因子 A 的启动子结合，促进血管生成。此外，SPI1CD68 TAMs 浸润水平与免疫治疗的疗效密切相关，尤其是与抗血管生成治疗联合使用时。
本研究表明，SPI1CD68 TAMs 是预测 GC 患者预后、抗血管生成药物敏感性和免疫治疗联合靶点的有前途的生物标志物。
