Australian scientists have identified the TAK1 gene as a significant factor that helps cancer cells survive attacks from the immune system, potentially limiting the effectiveness of immunotherapy treatments.
A research team at the Olivia Newton-John Cancer Research Institute (ONJCRI) and WEHI found that TAK1 acts as a protective mechanism for cancer cells against CD8⁺ T cell activity. These T cells are key components of the immune response that target and kill abnormal cells, including those found in tumors.
The researchers conducted a genetic screen to identify genes that help cancer cells withstand immune attack. They discovered that when TAK1 was silenced using CRISPR/Cas9 technology in pre-clinical models with functioning immune systems, tumors without this gene grew poorly. This suggested that blocking TAK1 allows the immune system to control cancer growth more effectively.
Dr Anne Huber, a postdoctoral researcher at ONJCRI and La Trobe University's School of Cancer Medicine, explained: "It is known that TAK1 promotes cancer cell survival and blocks cell death, however we didn't know that cancer cells use this tactic to avoid killing by the immune system."
She added: "When TAK1 was blocked, immune signals generated by CD8+ T cells triggered the cancer cell's self-destruct pathways. Without TAK1, the cancer cells lose a key protein, cFLIP, that normally prevents cell death, and they become far more sensitive to immune attack."
Dr Tirta (Mario) Djajawi from ONJCRI noted: "Blocking TAK1 could make current immunotherapies more effective by stripping tumours of this protection. TAK1 is like a shock absorber that lets cancer cells survive the immune system's hardest hits. Remove it, and the tumour collapses under the force of immune attack."
The study included various types of cancers but focused mainly on melanoma—a disease diagnosed in 330,000 people globally each year and responsible for about 60,000 deaths annually as of 2022.
The next phase of research will investigate ways to block TAK1 using liquid nanoparticle technology while also testing how existing immunotherapies perform against cancer cells lacking this gene.
This project involved collaboration with Dr Stephin Vervoort's laboratory and Sarahi Mendoza Rivera at WEHI.
