All of us produce a growth factor – called IL-15 – which effectively protects us from cancers. It's role is to boost the production of immune cells that can rapidly detect and kill cancer cells when they first appear. One of these cell-types is appropriately called Natural Killer Cells.
The problem is that cancer cells evolve numerous strategies to suppress immune cells like NK cells, even when these cancer cell are producing the immune boosting factor IL-15, and too often the cancer cells win. An obvious solution is to supply cancer patients with drugs that trigger the IL-15 receptor on immune cells, however these approaches have proven too toxic for patients because they boosts the activity of immune cells in every tissue, not just in the tumour, resulting in severe side-effects.
Until now.
A team of researchers at Monash University and oNKo-Innate in Melbourne, Australia have found a gene that can be switched off in NK cells which makes them extremely sensitive to the body's own IL-15, opening the way for the development of a new therapy to treat cancer.
The study, led by Professor Nick Huntington, from the Monash Biomedicine Discovery Institute and the team at Melbourne-based biotech oNKo-Innate, and published in the leading international cancer journal, Cancer Cell, showed that switching this gene off in human NK cells dramatically boosted their sensitivity to low amounts of IL-15, resulting in enhanced anti-cancer function and slowing the growth of colorectal cancer in pre-clinical models.
Importantly this gene encodes an enzyme, meaning that it can potentially be inhibited with small molecule drugs. In fact, another drug that blocks the function of this molecular pathway, in addition to others, has already been tested in patients with myelodysplastic syndrome to induce cancer cell death "which gives us some confidence that more specific inhibitors can be discovered with improved safety profiles to be tested in settings where immunotherapy is sub-optimal and additional ways to enhance the immune response to cancer are needed" Professor Huntington said.
In patients with colorectal cancers, the tumour cells produce higher amounts of IL-15 than other healthy tissues in their body. Cancer cells can often mutate the IL-15 gene to blunt the immune response and this is linked to tumour recurrence and a poor prognosis in these patients. Making immune cells exquisitely sensitive to the body's own IL-15 has the potential to drive strong immune activation at sites of IL-15 such as colorectal cancer, while sparing other healthy organs where IL-15 levels are negligible.
The researchers used CRISPR screening to find genes that enhanced the sensitivity of immune cells to growth factors finding two genes that can be deleted in cell therapies or inhibited with small molecule drugs to improve the cancer killing activity of NK cells.
Importantly, this newly identified way to harness the normal IL-15 pathway could be used in combination with existing gold-standard cancer immune checkpoint inhibitors, according to Jai Rautela, CEO of oNKo-Innate. "Drugs that augment IL-15 signalling could add yet another layer of support to the anti-cancer immune activity in advanced tumours," he said.
"This study is an important demonstration that deep immunology can generate new solutions to historically difficult biology, such as IL-15, and pave the way for next-generation immunotherapies."
Read the full paper in Cancer Cell: Enhancing Anti-Tumor Immunity of Natural Killer Cells through Targeting IL-15R Signaling. DOI: 10.1016/j.ccell.2025.05.011
