Combination therapy with anti-HER2 agents and immunotherapy has demonstrated significant clinical benefits in gastric cancer (GC), but the underlying mechanism remains unclear. In this study, we used multiplex immunohistochemistry to assess the changes of the tumor microenvironment in 47 advanced GC patients receiving anti-HER2 therapy. Additionally, we performed single-cell transcriptional sequencing to investigate potential cell-to-cell communication and molecular mechanisms in four HER2-positive GC baseline samples. We observed that post-treated the infiltration of NK cells, CD8⁺ T cells, and B lymphocytes were significantly higher in patients who benefited from anti-HER2 treatment than baseline. Further spatial distribution analysis demonstrated that the interaction scores between NK cells and CD8⁺ T cells, B lymphocytes and M2 macrophages, B lymphocytes and Tregs were also significantly higher in benefited patients. Cell–cell communication analysis from scRNA sequencing showed that NK cells utilized CCL3/CCL4-CCR5 to recruit CD8⁺ T cell infiltration. B lymphocytes employed CD74-APP/COPA/MIF to interact with M2 macrophages, and utilized TNF-FAS/ICOS/TNFRSR1B to interact with Tregs. These cell–cell interactions contribute to inhibit the immune resistance of M2 macrophages and Tregs. Our research provides potential guidance for the use of anti-HER2 therapy in combination with immune therapy.

中文翻译：

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HER2阳性晚期胃癌肿瘤免疫微环境重塑及HER2靶向治疗的反应

抗 HER2 药物和​​免疫疗法的联合治疗已在胃癌 (GC) 中表现出显着的临床益处，但其潜在机制仍不清楚。在本研究中，我们采用多重免疫组织化学方法评估 47 例接受抗 HER2 治疗的晚期 GC 患者肿瘤微环境的变化。此外，我们还进行了单细胞转录测序，以研究四个 HER2 阳性 GC 基线样本中潜在的细胞间通讯和分子机制。^{我们观察到，受益于抗 HER2 治疗的患者治疗后 NK 细胞、CD8 +} T 细胞和 B 淋巴细胞的浸润显着高于基线。^{进一步的空间分布分析表明，受益患者中NK细胞与CD8 +} T细胞、B淋巴细胞与M2巨噬细胞、B淋巴细胞与Treg细胞之间的相互作用评分也显着较高。scRNA 测序的细胞间通讯分析表明 NK 细胞利用 CCL3/CCL4-CCR5 来招募 CD8 ⁺ T 细胞浸润。B淋巴细胞利用CD74-APP/COPA/MIF与M2巨噬细胞相互作用，利用TNF-FAS/ICOS/TNFRSR1B与Treg细胞相互作用。这些细胞间相互作用有助于抑制 M2 巨噬细胞和 Tregs 的免疫抵抗。我们的研究为抗 HER2 疗法与免疫疗法的联合使用提供了潜在的指导。