Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province 510515, China.
The fifth clinical school, Guangzhou Medical University, Guangzhou, Guangdong Province 511436, China; Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 511436, China.
Biochim Biophys Acta Mol Basis Dis. 2025 Jan;1871(1):167560. doi: 10.1016/j.bbadis.2024.167560. Epub 2024 Oct 30.
Gastric cancer (GC) is the fourth leading cause of cancer death worldwide. Due to the complex tumor microenvironment (TME), the efficacy of immunotherapy in GC has not met expectations. Malignant changes in the TME induce endoplasmic reticulum stress (ERS). ERS can be transmitted between tumor cells and tumor-associated macrophages (TAMs), promoting tumor immune escape, but the specific mechanism in GC remains unclear. We established a TAM model of transmitted ERS (TERS), and iTRAQ proteomic analysis identified overexpressed proteins. The overexpression of poliovirus receptor (PVR) was screened while flow cytometry and ELISA showed that PVR mediated the immunosuppressive function of TAMs by downregulating the proliferative activity and cytotoxicity of cocultured CD8+ T lymphocytes. With EMSA and dual-luciferase reporter assays, we confirmed that erythropoietin-producing hepatocellular receptor A2 (EphA2) affected PVR expression by increasing the transcriptional activity of activator protein-1 (AP-1). MFC cells were mixed with EphA2 knockdown or control RAW264.7 cells to establish subcutaneous tumor models with or without tunicamycin treatment in vivo. The vivo experiments revealed that ERS promoted subcutaneous xenograft growth, which was reversed by EphA2 knockdown. Clinically, GC patients with high expression of PVR and EphA2 tended to have an immunosuppressive TME, which were determined by immunohistochemical and immunofluorescence analyses. In conclusion, the transcriptional activity of AP-1 is upregulated in ERS-transmitted TAMs through EphA2 to increase PVR expression, which promotes immune escape in GC. Our study provides a new perspective on the role of ERS in tumor immunity.
胃癌（GC）是全球癌症死亡的第四大主要原因。由于肿瘤微环境（TME）复杂，免疫疗法在 GC 中的疗效并未达到预期。TME 的恶性变化会引起内质网应激（ERS）。ERS 可以在肿瘤细胞和肿瘤相关巨噬细胞（TAMs）之间传递，促进肿瘤免疫逃逸，但 GC 中的具体机制尚不清楚。我们建立了 TAM 传递的 ERS（TERS）模型，并通过 iTRAQ 蛋白质组分析鉴定了过度表达的蛋白质。流式细胞术和 ELISA 显示，通过下调共培养的 CD8+T 淋巴细胞的增殖活性和细胞毒性，PVR 介导了 TAMs 的免疫抑制功能，从而筛选出过表达的脊髓灰质炎病毒受体（PVR）。通过 EMSA 和双荧光素酶报告基因分析，我们证实了促红细胞生成素产生肝细胞受体 A2（EphA2）通过增加激活蛋白-1（AP-1）的转录活性来影响 PVR 的表达。将 MFC 细胞与 EphA2 敲低或对照 RAW264.7 细胞混合，在体内建立带有或不带有衣霉素处理的皮下肿瘤模型。体内实验表明，ERS 通过 EphA2 促进了皮下异种移植物的生长，而 EphA2 敲低则逆转了这一过程。临床上，GC 患者中高表达 PVR 和 EphA2 的患者倾向于具有免疫抑制性 TME，这通过免疫组织化学和免疫荧光分析来确定。总之，AP-1 的转录活性通过 EphA2 在 ERS 传递的 TAMs 中被上调，从而增加 PVR 的表达，促进 GC 中的免疫逃逸。我们的研究为 ERS 在肿瘤免疫中的作用提供了新的视角。
