Department of Surgery, The University of Melbourne, Austin Health, Lance Townsend Building, Level 8, 145 Studley Road, Heidelberg, VIC 3084, Australia.
Department of Infectious Diseases, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia.
Int J Mol Sci. 2022 May 9;23(9):5281. doi: 10.3390/ijms23095281.
(1) Liver regeneration following partial hepatectomy for colorectal liver metastasis (CRLM) has been linked to tumour recurrence. Inhibition of the renin−angiotensin system (RASi) attenuates CRLM growth in the non-regenerating liver. This study investigates whether RASi exerts an antitumour effect within the regenerating liver following partial hepatectomy for CRLM and examines RASi-induced changes in the tumour immune microenvironment; (2) CRLM in mice was induced via intrasplenic injection of mouse colorectal tumour cells, followed by splenectomy on Day 0. Mice were treated with RASi captopril (250 mg/kg/day), or saline (control) from Day 4 to Day 16 (endpoint) and underwent 70% partial hepatectomy on Day 7. Liver and tumour samples were characterised by flow cytometry and immunofluorescence; (3) captopril treatment reduced tumour burden in mice following partial hepatectomy (p < 0.01). Captopril treatment reduced populations of myeloid-derived suppressor cells (MDSCs) (CD11b+Ly6CHi p < 0.05, CD11b+Ly6CLo p < 0.01) and increased PD-1 expression on infiltrating hepatic tissue-resident memory (TRM)-like CD8+ (p < 0.001) and double-negative (CD4-CD8-; p < 0.001) T cells; (4) RASi reduced CRLM growth in the regenerating liver and altered immune cell composition by reducing populations of immunosuppressive MDSCs and boosting populations of PD-1+ hepatic TRMs. Thus, RASi should be explored as an adjunct therapy for patients undergoing partial hepatectomy for CRLM.
(1) 结直肠癌肝转移（CRLM）患者行部分肝切除术后的肝再生与肿瘤复发有关。肾素-血管紧张素系统（RAS）抑制剂可抑制非再生肝中的 CRLM 生长。本研究旨在探讨 RASi 在 CRLM 患者行部分肝切除术后再生肝中是否具有抗肿瘤作用，并研究 RASi 诱导的肿瘤免疫微环境变化；(2) 通过脾脏内注射小鼠结直肠肿瘤细胞诱导 CRLM，于第 0 天行脾切除术。从第 4 天到第 16 天（终点），小鼠用 RASi 卡托普利（250mg/kg/天）或生理盐水（对照）治疗，并于第 7 天行 70%部分肝切除术。通过流式细胞术和免疫荧光法对肝和肿瘤样本进行特征分析；(3) 卡托普利治疗可降低部分肝切除术后小鼠的肿瘤负担（p<0.01）。卡托普利治疗可减少髓系来源抑制细胞（MDSCs）的群体（CD11b+Ly6CHi，p<0.05；CD11b+Ly6CLo，p<0.01），并增加浸润性肝组织驻留记忆样 CD8+（TRM）（p<0.001）和双阴性（CD4-CD8-；p<0.001）T 细胞上的 PD-1 表达；(4) RASi 通过减少免疫抑制性 MDSCs 的群体并增加 PD-1+肝 TRM 的群体，降低了再生肝中的 CRLM 生长和改变了免疫细胞组成。因此，RASi 应作为 CRLM 患者行部分肝切除术后的辅助治疗进行探索。
