A new study led by King's College London has found that chemotherapy helps attract a specific population of immune cells called stem-like T cells towards tumours.
The research, published in Cell Stem Cell, found that macrophages around tumour blood vessels can act as a barrier, limiting their ability to enter. By blocking an enzyme called heme oxygenase-1 (HO-1) in these macrophages, the researchers were able to reduce this barrier, allowing more stem-like T cells to enter the tumour and contribute to an anti-tumour immune response. The findings could help explain differences in responses to chemotherapy and may also have implications for immunotherapies that depend on stem-like T cells.
T cells play an important role in the body's ability to recognise and attack cancer. Certain 'stem-like' T cells are particularly important because they can renew themselves and develop into other T cells that can attack cancer cells. They can therefore help sustain an immune response against a tumour over time and have also been shown to play an important role in responses to immunotherapy.
However, while we know these cells can be important in the immune response to cancer, less is understood about how they enter tumours and the barriers that may hinder their entry. The researchers found that a specific population of a type of white blood cell called macrophages, located around the tumour's blood vessels, can act as a kind of 'gatekeeper', controlling whether stem-like T cells can move from the bloodstream into the tumour.
They found that chemotherapy changes the tumour environment and increases signals that attract stem-like T cells towards the tumour. However, the cells still struggled to enter the tumour because of the barrier created by the macrophages.
It was an exciting and unexpected discovery that, despite its complexity, the tumour microenvironment can be targeted to help chemotherapy work better and engage the stem-like T cells."
Lead author Dr Tik Shing Cheung, Research Associate, King's College
The macrophages produce an enzyme called heme oxygenase-1 (HO-1). When the researchers blocked HO-1, this barrier was reduced, allowing more stem-like T cells to enter the tumour.
HO-1 inhibition alone was not sufficient to control tumour growth. However, when combined with chemotherapy, the two approaches worked together, as chemotherapy helped attract the stem-like T cells towards the tumour, while HO-1 inhibition helped them enter.
The researchers found that the T cells were recruited through a signalling pathway involving the chemokine CXCL12 and its receptor CXCR4. CXCL12 acts as a signal that attracts the T cells, while CXCR4 allows the T cells to respond to it.
Further research is needed to understand whether this mechanism operates in different types of cancer and whether the findings could eventually be translated into treatments for patients.
Stem-like T cells have become a really important cell of interest in the anti-tumour immune response. The observation that macrophages that reside close to blood vessels can hinder this effect via HO-1 is important as it provides a therapeutic target to improve their entry to tumours, which may improve responses to other immunotherapies, such as immune checkpoints, which rely on these cells for their therapeutic effect."
Senior author Professor James Arnold, Professor of Tumour Immunology, King's College London
The findings of this study provide new insight into how the tumour environment can control the immune response and could help researchers better understand how to enable cancer-fighting T cells to reach tumours. Researchers at King's are developing drugs that target HO-1, including a lead candidate being advanced by Aethox Therapeutics a spinout company from King's College London. Aethox is currently raising funding to support the development of the drug KCL-HO-1i towards clinical trials.
This research was supported by funding from Cancer Research UK, the Cancer Research UK City of London Centre, and the Cancer Research Institute, New York.
