Y Zhang1,2,3,4,5, Q Zhai6, X Feng1,2,3,4,5, D Chen1,2,3,4,5, Y Lu1,2,3,4,5, J Hu1,2,3,4,5, H Xie2,3,4, L Zhou2,3,4, J Wu7,8,9, S Zheng10,11,12,13. 1. Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China. 2. NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, 310003, China. 3. Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Hangzhou, 310003, China. 4. Key Laboratory of Organ Transplantation, Hangzhou, 310003, Zhejiang Province, China. 5. Zhejiang Provincial Research Center for Diagnosis and Treatment of Heapatobiliary Diseases, Hangzhou, 310003, China. 6. Department of Anesthesiology & Center for Brain Science, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China. 7. Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China. drwujian@zju.edu.cn. 8. Key Laboratory of Organ Transplantation, Hangzhou, 310003, Zhejiang Province, China. drwujian@zju.edu.cn. 9. Zhejiang Provincial Research Center for Diagnosis and Treatment of Heapatobiliary Diseases, Hangzhou, 310003, China. drwujian@zju.edu.cn. 10. Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China. shusenzheng@zju.edu.cn. 11. NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, 310003, China. shusenzheng@zju.edu.cn. 12. Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Hangzhou, 310003, China. shusenzheng@zju.edu.cn. 13. Key Laboratory of Organ Transplantation, Hangzhou, 310003, Zhejiang Province, China. shusenzheng@zju.edu.cn.
Abstract
PURPOSE: The activation of stimulator of interferon genes (STING) pathway triggers the antitumor immunity by CD8 + T cells. However, the differentiated antitumor effects of STING activation in different cell types is still unclear. We aimed to investigate the expression and potential prognostic value of cancer cell-intrinsic STING in hepatocellular carcinoma (HCC), and whether STING could be a potential immunotherapeutic target of HCC was then evaluated. METHODS: We separately assessed the expression of STING in cancer cells and infiltrating immune cells in HCC tissues. The independent clinicopathological factors associated with survival outcomes were evaluated by the multivariable analysis. The HCC orthotopic mice model were used to confirm the immunotherapeutic effects of STING agonists, and CD8 + T-cell infiltration level was analyzed through immunofluorescence and flow cytometry. RESULTS: The expression of cancer cell-intrinsic STING was significantly reduced in HCC compared with adjacent tissues. Patients with low levels of cancer cell-intrinsic STING expression was associated with increased tumor volume (P = 0.009), higher serum AFP levels (P = 0.028), and decreased CD8 + T-cell infiltration (P = 0.002). Low levels of cancer cell-intrinsic STING expression indicated a poor overall survival (OS) and disease-free survival (DFS). Multivariate analysis demonstrated that low levels of cancer cell-intrinsic STING expression was an independent prognostic factor. Additionally, cancer cell-intrinsic STING expression was positively related with CD8 + T-cell infiltration levels in HCC patients (r = 0.308; P = 0.001). When mice with orthotopic HCC tumors treated with STING agonists, tumor growth was significantly reduced with enhanced levels of CD8 + T-cell infiltration. CONCLUSION: Cancer cell-intrinsic STING might affect HCC tumor progression through enhancing CD8 + T-cell infiltration and can be an immunotherapeutic target for HCC.
PURPOSE: The activation of stimulator of interferon genes (STING) pathway triggers the antitumor immunity by CD8 + T cells. However, the differentiated antitumor effects of STING activation in different cell types is still unclear. We aimed to investigate the expression and potential prognostic value of cancer cell-intrinsic STING in hepatocellular carcinoma (HCC), and whether STING could be a potential immunotherapeutic target of HCC was then evaluated. METHODS: We separately assessed the expression of STING in cancer cells and infiltrating immune cells in HCC tissues. The independent clinicopathological factors associated with survival outcomes were evaluated by the multivariable analysis. The HCC orthotopic mice model were used to confirm the immunotherapeutic effects of STING agonists, and CD8 + T-cell infiltration level was analyzed through immunofluorescence and flow cytometry. RESULTS: The expression of cancer cell-intrinsic STING was significantly reduced in HCC compared with adjacent tissues. Patients with low levels of cancer cell-intrinsic STING expression was associated with increased tumor volume (P = 0.009), higher serum AFP levels (P = 0.028), and decreased CD8 + T-cell infiltration (P = 0.002). Low levels of cancer cell-intrinsic STING expression indicated a poor overall survival (OS) and disease-free survival (DFS). Multivariate analysis demonstrated that low levels of cancer cell-intrinsic STING expression was an independent prognostic factor. Additionally, cancer cell-intrinsic STING expression was positively related with CD8 + T-cell infiltration levels in HCC patients (r = 0.308; P = 0.001). When mice with orthotopic HCC tumors treated with STING agonists, tumor growth was significantly reduced with enhanced levels of CD8 + T-cell infiltration. CONCLUSION: Cancer cell-intrinsic STING might affect HCC tumor progression through enhancing CD8 + T-cell infiltration and can be an immunotherapeutic target for HCC.
Entities:
Keywords:
CD8 + T cell; Hepatocellular carcinoma; Immunotherapy; Prognosis; STING