Type I interferon (IFN-I) and IFN-γ can promote anti-tumor immunity by promoting the body's T cell response. Paradoxically, IFN-γ can promote T cell exhaustion by activating immune checkpoints, and the downstream regulatory mechanisms of these different responses are still unclear to researchers. Recently, in a research report entitled "Opposing tumor-cell-intrinsic and -extrinsic roles of the IRF1 transcription factor in antitumor immunity" published in the international journal Cell Reports, scientists from the David Geffen School of Medicine at the University of California and other institutions revealed the role and details of a special protein called interferon regulatory factor (IRF1) in cancer progression and response to therapy, which is expected to provide new insights to help improve the efficacy of cancer immunotherapy.
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In the article, researchers revealed how IRF1 hinders and helps the body's immune response against tumors, depending on which cells the IRF1 protein is found in. Professor Philip Scumpia said, "We all know that IRF1 plays a vital role in regulating the body's anti-tumor immunity. However, there are still conflicting reports about whether IRF1 promotes or inhibits the body's anti-tumor immunity. To our surprise, the effect of IRF1 depends on the cells that express it, which may explain these conflicting reports."
Figure 1. While IRF1 in immune cells is required for antitumor immunity, tumor cell IRF1 suppresses Toll-like receptors and interferon-induced antitumor lymphocyte activation and regulates select immunosuppressive and MHC genes in interferon-stimulated tumor cells. (Purbey P K, et al. 2024)
Today, immunotherapy remains a powerful approach in cancer treatment, harnessing the body's immune system to recognize and attack cancer cells. Although immunotherapy can successfully treat certain types of cancer and induce long-term disease remission in some patients, it still does not work for all patients. Understanding the mechanisms by which proteins such as IRF1 work could help improve human immunotherapy strategies and make them effective for a wider range of patients. To understand the key role IRF1 plays in tumor growth and immune responses, the researchers looked at what happens when IRF1 is missing in tumor cells and surrounding cells.
"We previously found that cells exposed to ionizing radiation (a well-known cancer treatment) can induce an immune response through IRF1, so we wanted to see if IRF1 could also mediate a similar immune response in growing tumors," said researcher Prabhat Purbey. First, the researchers developed IRF1-deficient clones of multiple tumor cells and compared the growth of these genetically modified tumors with that of normal tumors. Then, histology and flow cytometry were used to assess the infiltration of immune cells. The researchers further analyzed the effects of immune checkpoint blockade therapy (a type of immunotherapy) on these tumors and performed single-cell RNA sequencing to understand the activation state of immune cells.
The researchers found that the presence of IRF1 in tumor cells can actually weaken the host's immune response by promoting T cell exhaustion and affecting toll-like receptor and type I interferon responses. This is because IRF1 in tumor cells can increase the levels of multiple immune checkpoints, including IDO-1 and PD-L1, which inhibit T cell activity, and can change the expression of proteins involved in antigen presentation. However, IRF1 is essential for the development and recruitment of immune cells and the function of cytotoxic T cells and natural killer cells. Cytotoxic T cells and natural killer cells are key immune cells that can directly attack tumor cells.
"These findings suggest that reducing IRF1 levels in tumor cells or activating it in immune cells can enhance the effectiveness of cancer treatments by enhancing the body's natural anti-tumor immunity," said Scumpia. "We now have a clearer understanding of where IRF1 affects the effectiveness of immunotherapy and how to adjust it to help protect against cancer."
Although more research is needed to clarify whether targeting IRF1 in tumor cells or immune cells can have benefits after tumors have grown. But this research may help clarify why IRF1 proves to be a hindrance or a help in different cancer situations. The potential to manipulate IRF1 in a specific way could change the way we approach cancer immunotherapy.
Reference
Purbey P K, et al. Opposing tumor-cell-intrinsic and-extrinsic roles of the IRF1 transcription factor in antitumor immunity. Cell Reports, 2024, 43(6).