Tumor-secreted IFI35 promotes proliferation and cytotoxic activity of CD8(+) T cells through PI3K/AKT/mTOR signaling pathway in colorectal cancer

BACKGROUND: A large proportion of the patients with cancer do not respond to immunotherapies. Recent studies suggested an important role for tumor-infiltrating 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 effect 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 effect on anti-tumor immunity in both immunodeficient 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 efficacy 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 infiltration and predicted a better outcome in colorectal cancer. The number and cytotoxicity of CD8(+) T cells were significantly increased in IFI35-overexpressing tumors. Mechanistically, we identified 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 efficacy of CAR-T cells against colorectal cancer cells. CONCLUSION: Our findings identify IFI35 as a new biomarker that can enhance the proliferation and function of CD8(+) T cells, as well as increase the efficacy of CAR-T cells against colorectal cancer cells. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12929-023-00930-6.