BACKGROUND It is now recognized that many anticancer treatments positively modulate the antitumor immune response. Clinical and experimental studies have shown that inhibitors of the classical renin-angiotensin system (RAS) reduce tumor progression and are associated with better outcomes in patients with colorectal cancer. RAS components are expressed by most immune cells and adult hematopoietic cells, thus are potential targets for modulating tumor-infiltrating immune cells and can provide a mechanism of tumor control by the renin-angiotensin system inhibitors (RASi). AIM To investigate the effects of the RASi captopril on tumor T lymphocyte distribution in a mouse model of colorectal liver metastases. METHODS Liver metastases were established in a mouse model using an autologous colorectal cancer cell line. RASi (captopril 750 mg/kg) or carrier (saline) was administered to the mice daily via intraperitoneal injection, from day 1 post-tumor induction to endpoint (day 15 or 21 post-tumor induction). At the endpoint, tumor growth was determined, and lymphocyte infiltration and composition in the tumor and liver tissues were analyzed by flow cytometry and immunohistochemistry (IHC). RESULTS Captopril significantly decreased tumor viability and impaired metastatic growth. Analysis of infiltrating T cells into liver parenchyma and tumor tissues by IHC and flow cytometry showed that captopril significantly increased the infiltration of CD3+ T cells into both tissues at day 15 following tumor induction. Phenotypical analysis of CD45+ CD3+ T cells indicated that the major contributing phenotype to this influx is a CD4 and CD8 double-negative T cell (DNT) subtype, while CD4+ T cells decreased and CD8+ T cells remained unchanged. Captopril treatment also increased the expression of checkpoint receptor PD-1 on CD8+and DNT subsets . CONCLUSION Captopril treatment modulates the immune response by increasing the infiltration and altering the phenotypical composition of T lymphocytes and may be a contributing mechanism for tumor control.

中文翻译：

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肾素-血管紧张素系统抑制剂对结直肠肝转移小鼠T淋巴细胞的免疫调节作用。

背景技术现在已经认识到，许多抗癌治疗积极地调节抗肿瘤免疫应答。临床和实验研究表明，经典的肾素-血管紧张素系统（RAS）抑制剂可降低肿瘤的进展，并与结直肠癌患者的预后更好相关。RAS成分在大多数免疫细胞和成年造血细胞中表达，因此是调节肿瘤浸润免疫细胞的潜在靶点，并且可以通过肾素-血管紧张素系统抑制剂（RASi）提供肿瘤控制机制。目的研究RASi卡托普利对结直肠肝转移小鼠模型中肿瘤T淋巴细胞分布的影响。方法使用自体结直肠癌细胞系在小鼠模型中建立肝转移。从肿瘤诱导后第1天至终点（肿瘤诱导后第15或21天）每天通过腹膜内注射向小鼠施用RASi（卡托普利750mg / kg）或载体（盐水）。在终点处，确定肿瘤的生长，并通过流式细胞术和免疫组织化学（IHC）分析肿瘤和肝脏组织中的淋巴细胞浸润和组成。结果卡托普利显着降低了肿瘤的生存能力并损害了转移性生长。通过IHC和流式细胞仪分析了浸润性T细胞进入肝实质和肿瘤组织后，卡托普利在诱导肿瘤后第15天显着增加了CD3 + T细胞对两种组织的浸润。CD45 + CD3 + T细胞的表型分析表明，对该流入的主要贡献表型是CD4和CD8双阴性T细胞（DNT）亚型，而CD4 + T细胞减少而CD8 + T细胞保持不变。卡托普利治疗还增加了CD8 +和DNT亚型上检查点受体PD-1的表达。结论卡托普利治疗可通过增加T淋巴细胞的浸润和改变表型组成来调节免疫应答，并且可能是控制肿瘤的一个重要机制。