Unveiling IRF1's Influence on Cancer Progression and Treatment Using Histology and Flow Cytometry

Researchers at the UCLA Health Jonsson Comprehensive Cancer Center have discovered new information regarding the function of a protein known as interferon regulatory factor (IRF1) in the course of cancer and how it responds to treatment. This information may help increase the efficacy of cancer immunotherapy.

The research, which was published in Cell Reports, shows how, depending on which cells the protein is present in, IRF1 can both aid and impede the body's immune response to tumors.

We know IRF1 plays a pivotal role in modulating antiviral immunity. But there were conflicting reports about whether IRF1 promotes or suppresses antitumor immunity. What was surprising to us was that the role of IRF1 was different depending upon which cells expressed it, potentially explaining the conflicting reports. Our findings add a layer of complexity to our understanding of IRF1 and its role in immunotherapy.”

Dr. Philip Scumpia, Associate Professor and Study Senior Author, David Geffen School of Medicine, UCLA Health

Immunotherapy is still a highly effective cancer treatment strategy. It functions by utilizing the immune system of the body to identify and combat cancerous cells. Immunotherapy does not always work, even though it has been successful in treating some cancers and in some cases, can cause a patient to go into long-term remission.

Scumpia pointed out that by better understanding the mechanisms of proteins like IRF1, immunotherapy strategies can be improved and made more effective for a wider variety of patients.

To analyze IRF1's function in immune response and tumor growth, the research team examined the consequences of IRF1 loss in tumor cells as well as adjacent cells.

We previously showed that cells exposed to ionizing radiation, a well-known treatment for cancer, induced an immune response through IRF1. We wanted to see whether IRF1 regulated similar immune responses in growing tumors.”

Dr. Prabhat Purbey, Project Scientist and Study First Author, Jonsson Comprehensive Cancer Center, UCLA Health

The researchers started by cloning different tumor cells with IRF1 deficiency and comparing the growth of these genetically altered tumors to those of normal tumors. They also evaluated immune cell infiltration using histology and flow cytometry.

Next, they used single-cell RNA sequencing to determine the immune cell activation states and looked at the impact of immune checkpoint blockade therapy, a form of immunotherapy, on these tumors.

They discovered that IRF1 in tumor cells could actually reduce the strength of the immune response by altering type-I interferon and toll-like receptor responses and encouraging T cell exhaustion.

This occurs as a result of IRF1's elevation in tumour cells of multiple immune checkpoints, such as PD-L1 and IDO-1, which modify the expression of proteins involved in antigen presentation while suppressing T-cell activity.

However, IRF1 is essential for the growth, attraction, and operation of natural killer cells and cytotoxic T cells—two important immune cells that can target the tumor directly.

These findings suggest that reducing IRF1 in tumor cells, or activating it in immune cells, could enhance cancer treatment effectiveness by boosting the body’s natural antitumor immunity. We now have a clearer picture of where IRF1 can impact immunotherapy and how we can tune it to help in the fight against cancer.”

Dr. Philip Scumpia, Associate Professor and Study Senior Author, David Geffen School of Medicine, UCLA Health

This research has clarified the reasons why IRF1 was demonstrated to help or hinder various cancer scenarios, even though more research is required to determine whether targeting IRF1 in tumor cells or immune cells will be beneficial after a tumor has grown in the body.

“The potential to manipulate IRF1 in specific ways could change the way we approach cancer immunotherapy. Our goal is to translate these findings into treatments that offer real hope and improved outcomes for cancer patients,” said Scumpia.