Cancer is often described as a battle between tumours and the immune system. But tumours do not merely sit passively while immune cells attack them. They can alter their surroundings and, in some cases, their own biology to make themselves harder for the immune system to recognise and destroy.
A new study published in Nature Communications has identified a previously underappreciated mechanism that may help colorectal cancer do just that.
Researchers led by Dr Takumi Itoh at Juntendo University found that interleukin-26 (IL-26), an inflammatory protein produced by immune cells, can enter the nucleus of colorectal cancer cells and alter their gene regulation. These changes appear to create an environment that is more favourable to tumour survival and less favourable to an effective immune response.
The findings could help explain one of the major challenges in cancer treatment: why some tumours fail to respond to immunotherapy, or become resistant after initially responding.
IL-26 belongs to the interleukin family of signalling proteins involved in communication between cells of the immune system. Inflammation is a normal component of the body's defence mechanisms, but persistent inflammation can also influence how tumours grow and interact with surrounding tissues. In the new study, researchers found that IL-26 has a more direct effect on cancer cells than previously appreciated. Rather than acting only through immune cells, the protein was found to enter colorectal cancer cells and reach their nuclei.
There, it triggered epigenetic changes, which are alterations that affect which genes are switched on or off without changing the underlying DNA sequence. These changes effectively helped cancer cells adopt an immune-evasive state.
One of the consequences was an increase in signals that attract neutrophils, a type of white blood cell. Although neutrophils are important components of the body's defence system, within the tumour microenvironment certain neutrophil populations can have immunosuppressive and tumour-promoting effects.
The researchers found that this neutrophil-rich environment could suppress the activity of T cells, the immune cells that can recognise and kill cancer cells.
Immune checkpoint inhibitors such as anti-PD-1 drugs work by releasing one of the brakes that cancer can place on T cells. But checkpoint inhibitors do not work equally well in all colorectal cancers.
A major determinant is the nature of the tumour's immune microenvironment—whether immune cells can enter the tumour and whether they remain capable of mounting an effective attack.
The new findings suggest that IL-26 may contribute to a hostile environment in which T cells are suppressed, potentially helping colorectal tumours resist anti-PD-1 treatment.
In preclinical experiments, the researchers found that blocking IL-26 or interfering with the downstream pathway it activates could restore anti-tumour immune activity. The experimental models also showed renewed responsiveness to immunotherapy.
This is particularly significant because it points towards a strategy that is different from simply developing another checkpoint inhibitor. Instead, the idea is to target the inflammatory and epigenetic mechanisms that prevent checkpoint therapy from working effectively in the first place.
The findings, however, are still at the preclinical stage. Results obtained in experimental models do not automatically translate into an effective or safe treatment for patients.
The next challenge will be to establish whether the IL-26 pathway plays the same role in human colorectal cancers, which patients are most likely to benefit from targeting it, and whether an IL-26-directed treatment can be safely combined with existing immunotherapies.
Dr Takumi Itoh, the study's lead researcher, said that therapeutic strategies aimed at blocking IL-26 or preventing the epigenetic changes it induces could potentially improve the effectiveness of immunotherapy in treatment-resistant cancers.
The research also highlights a broader question in cancer biology: that inflammation is not always simply an immune response against a tumour; under certain circumstances, it can become part of the machinery that protects the tumour from the immune system.
Understanding that switch could be crucial to making immunotherapy work for more patients with colorectal cancer and potentially other cancers in which inflammation and immune evasion are closely intertwined.
