Gastric cancer (GC) is the fourth most common cause of cancer-related death globally. The classification of advanced GC (AGC) according to molecular features has recently led to effective personalized cancer therapy for some patients. Specifically, AGC patients whose tumor cells express high levels of human epidermal growth factor receptor 2 (HER2) can now benefit from trastuzumab, a humanized monoclonal Ab that targets HER2. However, patients with HER2^negative AGC receive limited clinical benefit from this treatment. To identify potential immune therapeutic targets in HER2^negative AGC, we obtained 40 fresh AGC specimens immediately after surgical resections and subjected the CD45⁺ immune cells in the tumor microenvironment to multi-channel/multi-panel flow cytometry analysis. Here, we report that HER2 negativity associated with reduced overall survival (OS) and greater tumor infiltration with neutrophils and non-classical monocytes. The potential pro-tumoral activities of these cell types were confirmed by the fact that high expression of neutrophil or non-classical monocyte signature genes in the gastrointestinal tumors in The Cancer Genome Atlas, Genotype-Tissue Expression and Gene Expression Omnibus databases associated with worse OS on Kaplan-Meir plots relative to tumors with low expression of these signature genes. Moreover, advanced stage disease in the AGCs of our patients associated with greater tumor frequencies of neutrophils and non-classical monocytes than early stage disease. Thus, our study suggests that these 2 myeloid populations may serve as novel therapeutic targets for HER2^negative AGC.

中文翻译：

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肿瘤浸润的中性粒细胞和非经典单核细胞可能是 HER2 阴性胃癌的潜在治疗靶点。

胃癌 (GC) 是全球癌症相关死亡的第四大常见原因。根据分子特征对晚期 GC (AGC) 进行分类最近为一些患者带来了有效的个性化癌症治疗。具体来说，肿瘤细胞表达高水平人表皮生长因子受体 2 (HER2) 的 AGC 患者现在可以从曲妥珠单抗中受益，曲妥珠单抗是一种靶向 HER2 的人源化单克隆抗体。然而，HER2^阴性AGC患者从这种治疗中获得的临床益处有限。为了确定 HER2^阴性AGC 中潜在的免疫治疗靶点，我们在手术切除后立即获得了 40 个新鲜的 AGC 标本，并进行了 CD45 ⁺肿瘤微环境中的免疫细胞进行多通道/多面板流式细胞术分析。在这里，我们报告了 HER2 阴性与降低的总生存率 (OS) 和更大的肿瘤浸润与中性粒细胞和非经典单核细胞相关。这些细胞类型的潜在促肿瘤活性通过以下事实得到证实：癌症基因组图谱、基因型-组织表达和基因表达综合数据库中胃肠道肿瘤中中性粒细胞或非经典单核细胞特征基因的高表达与较差的 OS 相关在 Kaplan-Meir 图上，这些特征基因的表达较低。此外，与早期疾病相比，我们患者的 AGC 中的晚期疾病与更高的中性粒细胞和非经典单核细胞的肿瘤频率相关。因此，^负AGC。