- 作者: Peisi Li, Dawang Zhou, Dongwen Chen, Yikan Cheng, Yuan Chen, Zhensen Lin, Xi Zhang, Zhihong Huang, Jiawei Cai, Wenfeng Huang, Yanyun Lin, Haoxian Ke, Jiahui Long, Yifeng Zou, Shubiao Ye & Ping Lan
- 作者服務機構: 1.Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China 2.Department of General Surgery (Department of Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangdong, Guangzhou, People’s Republic of China 3.Department of Hepatobiliary and Pancreatic Surgery, Sun Yat-Sen University Cancer Center, Guangdong, Guangzhou, People’s Republic of China 4.Department of Radiation Oncology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, People’s Republic of China 5.Guangdong Institute of Gastroenterology; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, People’s Republic of China 6.Guangzhou Biosyngen Co., Ltd., Guangdong, People’s Republic of China 7.School of Medicine, Sun Yat-Sen University, Shenzhen, Guangdong, People’s Republic of China 8.State Key Laboratory of Oncology in South China, Sun Yat-sen University, Guangzhou, People’s Republic of China
- 中文摘要:
- 英文摘要:
Background A large proportion of the patients with cancer do not respond to immunotherapies. Recent studies
suggested an important role for tumor-infltrating cytotoxic T lymphocytes (CTL) in enhancing response to immunotherapy. Here, we aim to identify gene that induce proliferative and cytotoxic states of CD8+ T cells, and to investigate
its efect on CAR-T cells against colorectal cancer.
Methods Correlation between the expression of IFI35 with the activation and cytotoxicity of CD8+ T cells was
assessed with TCGA and proteomic databases. Then we constructed murine colon cancer cells over-expressing IFI35
and tested their efect on anti-tumor immunity in both immunodefcient and immunocompetent mouse models.
Flow cytometry and immunohistochemistry were performed to assess the immune microenvironment. Western blot
analysis was used to identify the potential down-stream signaling pathway regulated by IFI35. We further investigated
the efcacy of the rhIFI35 protein in combination with immunotherapeutic treatment.
Results The transcriptional and proteomic analysis of the activation and cytotoxicity of CD8+ T cells in human cancer
samples demonstrated that IFI35 expression is correlated with increased CD8+ T cell infltration and predicted a better
outcome in colorectal cancer. The number and cytotoxicity of CD8+ T cells were signifcantly increased in IFI35-overexpressing tumors. Mechanistically, we identifed that the IFNγ-STAT1-IRF7 axis stimulated IFI35 expression, and that
IFI35-mediated regulation of CD8+ T cell proliferation and cytotoxicity was dependent on PI3K/AKT/mTOR signaling
pathway in vitro. Furthermore, IFI35 protein enhanced the efcacy of CAR-T cells against colorectal cancer cells.
Conclusion Our fndings identify IFI35 as a new biomarker that can enhance the proliferation and function of CD8+ T
cells, as well as increase the efcacy of CAR-T cells against colorectal cancer cells. - 中文關鍵字:
- 英文關鍵字: s IFI35, CD8+ T cells, Immunotherapy, Colorectal cancer