Cyclooxygenase-2 expressing hepatocellular carcinoma inhibits the infiltration and immune response of conventional type 1 dendritic cells
10.3760/cma.j.cn113855-20240229-00146
- VernacularTitle:肝细胞癌中环氧合酶-2表达抑制常规1型树突状细胞的瘤内富集及免疫应答的研究
- Author:
Yuzi LI
1
;
Yang WANG
;
Qian CHENG
;
Zuyin LI
;
Zhao LI
;
Jiye ZHU
;
Jie GAO
Author Information
1. 北京大学人民医院肝胆外科，北京 100044
- Keywords:
Carcinoma,hepatocellular;
Dendritic cells;
COX-2;
Immune response
- From:
Chinese Journal of General Surgery
2024;39(5):372-378
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To investigate the influence of COX-2 expression in hepatocellular carcinoma (HCC) on the infiltration and immune response of conventional type 1 dendritic cells (cDC1).Methods:Clinicopathological data from 111 HCC patients undergoing radical hepatectomy at Peking University People's Hospital from Jan 2016 to Jun 2017 were retrospectively analyzed. Immunofluorescence staining was employed to evaluate the cDC1 infiltration and COX-2 expression in tumor tissues. Patients were divided into two groups based on cDC1 infiltration: cDC1 enrichment and cDC1 depletion, and the correlation between COX-2 expression and cDC1 infiltration was analyzed. Single-cell sequencing of HCC tumor tissues was used to further investigate the correlation between PTGS2, the encoding gene of COX-2, and cDC1 infiltration. Hematopoietic stem cells (HSC) were utilized for in vitro generation of cDC1. HSC-derived cDC1s were sorted by FACS and cocultured with HCC cell line SNU423. Celecoxib, a selective COX-2 inhibitor, was used to suppress the COX-2 expression in HCC cell line SNU423. The functions of cDC1 were explored by FITC-dextran uptake assay, flow cytometry, and Luminex multiplex cytokine assay. Results:COX-2 expression was significantly higher in the cDC1 depletion group ( n=73) compared to the cDC1 enrichment group ( n=38) ( P=0.004 2). Patients with higher PTGS2 expression had significantly lower proportion of cDC1. Increased cDC1 infiltration in the HCC tumor microenvironment correlated with improved patient overall survival rates ( P=0.037) and disease-free survival rates ( P=0.048). Results from FITC-dextran uptake assay, flow cytometry, and Luminex assay indicated that cDC1 co-cultured with HCC showed significantly reduced antigen uptake function, co-stimulatory molecule expression, and cytokine secretion, but partially abrogated with celecoxib treatment. Conclusions:The intratumoral infiltration of cDC1 is positively correlated with favorable prognosis in HCC patients. Elevated COX-2 expression in HCC impedes the intratumoral accumulation of cDC1 and compromises their immune response capabilities. COX-2 inhibitors hold promise for enhancing cDC1 function in HCC.
