The intrinsic pro-tumorigenic role of IRF1

Abstract

Abstract Interferon regulatory factor 1 (IRF1) is a nuclear transcription factor which appears to have anti-tumor activity in human and mice. IRF1 can be induced by interferon-gamma (IFNγ). Although recent studies indicated that the IFNγ-PD-L1 axis played an important role during T cell exhaustion, and promoted tumorigenesis, the cell intrinsic role of IRF1 is not completely clear in this context. In this study, we investigated the intrinsic role of IRF1 during tumor progression. We generated several IRF1-deficient (IRF1-KO) murine tumor cell lines (CT26, MC38 and B16-F10) via CRISPR/Cas9-mediated genome editing, and compared their growth rates with wild type (WT) cells both in vitro and in vivo using syngeneic mouse tumor models. We found that the loss of IRF1 did not affect cell growth rates in vitro. However, the IRF1-KO cells showed significantly slower tumor growth than WT cells in mice models. Depletion of CD8+ T cell using antibody rescued the ability of IRF1-KO cells to grow tumors. Furthermore, analysis of tumor infiltrating T cells showed more activated CD8+ T cells and less exhausted T cells in IRF1-KO induced tumors than those induced by WT cells. To confirm whether these results were caused by IFNγ-IRF1-PD-L1 axis, we evaluated IFNγ-induced inhibitory ligands on tumor cells in both WT and IRF1 KO cell lines. We found that the expression levels of MHC class I were not affected by loss of IRF1, whereas, the induction of PD-L1 by IFNγ was abolished in IRF1 KO cells. In conclusion, intrinsic loss of IRF1 in tumor cells significantly reduces tumorigenesis in solid tumors. This phenomenon depends on the regulation of PD-L1 expression on tumor cells via IFNγ-IRF1-PD-L1 axis, and eventually affecting host anti-tumor immune responses, such as CD8+ T cells.