Research has revealed that the role of an important protein in colorectal cancer may vary significantly depending on which cells it is active in.
The study, published in the journal npj Precision Oncology, shows that activity of a protein called mTOR may be associated with a stronger immune response in colorectal cancer when it is active in immune cells.
Mechanistic target of rapamycin, or mTOR, is a protein that plays an important role in cell signalling - a system of molecular messages that allows cells to regulate various biological functions. mTOR helps cells respond to nutrients and environmental conditions and influences growth, proliferation and immune activity. Because cancer cells often depend on these processes to grow and divide, mTOR signalling is common feature in many cancers.
Our findings show that mTOR signalling can have very different effects depending on which cells it is active in. In colorectal cancer, we found that activity in immune cells was associated with a stronger immune response and better patient survival, highlighting the importance of understanding signalling within the wider tumour environment."
Dr Heba Sailem, Reader in Computational Pathology, King's College London
One way researchers can tell that mTOR signalling is active is by checking to see whether proteins downstream of it have a phosphate group added - a process called phosphorylation. The researchers in this study were particularly interested in phosphorylated 4EBP1, a marker associated with mTOR activity.
Previous studies looking at p4EBP1 levels across the whole tumour have produced conflicting results about whether mTOR activity suppress or supports the growth of cancer. This paper, however, investigated whether the biological effect may depend heavily on whether p4EBP1 is present in cancer cells, stromal cells or immune cells. By looking at these different cell types simultaneously, the researchers were able to investigate mTOR activity not only in the cancer cells themselves, but across the wider tumour microenvironment.
The researchers analysed tissue from 746 colorectal tumours using highly multiplexed imaging capable of measuring 61 different protein markers at the same time. This allowed them to identify individual cancer cells, immune cells and stromal cells, while also measuring signalling of markers such as p4EBP1 and pS6.
They found that mTOR activity in immune cells was associated with better patient survival. Patients whose tumours contained immune cells positive for p4EBP1 lived roughly 9 months longer on average.
The researchers showed that immune cells in the tumour containing p4EBP1 had increased expression of genes associated with immune activation and function. They also found signals suggesting involvement of neutrophils, another type of immune cell.
The researchers believe the results could have implications for drugs designed to inhibit mTOR signalling in cancer. While mTOR activity can promote cancer-cell growth, the findings suggest that its activity in immune cells may also be associated with anti-tumour immune responses, meaning that blocking mTOR activity could have mixed effects.
Instead, new drugs may be able to target specific cells in patients, blocking mTOR from cells where it promotes cancer growth while preserving its activity in immune cells. As such, understanding these cell-specific differences could help inform more personalised approaches to treatment.
