Therapeutic potential for breast cancer found in the matrix

The interaction between cancer cells and the body’s immune system is a key determinant in patient survival. Many cancers have evolved the ability to effectively mask their presence and evade our immune system. As a result, the ability to ‘switch on’ the body’s immune response through immunotherapy, so that immune cells can attack and remove tumours, is a promising and growing area of cancer patient treatment and research.

Current immunotherapies used in the clinic focus on activating T cells (a type of white blood cell) through antigens on their cell surface enabling T cells within tumours to kill resident cancer cells.  However, this approach does not always work for all patients or tumour types, and has been associated with severe side effects.

Prof Kim Midwood, Kennedy Institute of Rheumatology, is instead looking into therapy opportunities in the space between cells, known as the extracellular matrix (ECM). The ECM is a three-dimensional network between cells, made up of extracellular macromolecules, such as collagens, enzymes, and glycoproteins, that provide structural and biochemical support to surrounding cells, as well as influencing the behaviour of the cells around it, such as cell survival and proliferation.

A recent study from Kim’s team, published in Cancer Immunology Research, investigated tumour-associated macrophages (TAMs) and the affect that the ECM has on them. Macrophages are specialised immune cells involved in the detection and destruction of harmful cells including bacteria and viruses that enter the body. In cancer, high levels of TAMs are generally associated with poor patient outcomes.  However, macrophage targeting treatments currently in development have had limited success.  One of the reasons for this is that TAMs are made up of a complicated mixture of many different types.  Whilst some macrophages protect the tumour and some fight the tumour, current therapies do not discriminate, instead blocking all TAM subsets.  Understanding more about type of TAMs therefore is required to enable therapies that only remove tumour-protecting subsets.

The tissue microenvironment is one factor that influences the functionality and type of macrophages.   Macrophages living in different tissues have very different functions, and these functions are programmed by the ECM of each specific tissue.  Most solid cancers are made up of a tumour-specific extracellular matrix that has a different composition and organization compared to that of healthy tissue. However, how this altered microenvironment affects macrophage behaviour is not fully understood.

Kim’s project investigated tenascin-C, a matrix molecule that is typically absent in the ECM of healthy tissues, but found in breast cancer , where it is often detected at high levels in people with poor disease outcomes, including breast cancers that grow and spread more quickly and have larger lung metastases. Tenascin-C’s role in tumour immunity was previously unclear, however Kim’s team have uncovered that it has therapeutic potential in breast cancer due to its ability to modulate macrophage (TAM) subtype.

They found that tenascin-C produced by tumour cells, rather than by healthy cells, promoted TAMs to assume a tumour protective, immune-system-suppressing behaviour.  Reversely, tenascin-C produced by healthy tissue promoted TAM behaviour that could attack and kill tumours.

This makes tenascin-C a potential therapeutic target for breast cancer treatment, as it has the capacity to drive both pro and anti-tumour macrophage behaviours, depending on its source. Already in development by Kim and her team is a therapeutic monoclonal antibody that has had pre-clinical success in the treatment of rheumatoid arthritis, and in this recent study was found to have immuno-oncology applications. Specifically, this antibody could block the ability of tenascin-C produced by the cancer cells to make TAMs protective, instead allowing TAMs to attack and kill tumours.  Treatment in pre-clinical models was effective in slowing tumour growth as well as stopping tumour metastasis, and when used together with existing checkpoint therapies, the combination of treatments was more effective than either treatment alone.

The next step for this new monoclonal antibody is to assess how it might be useful in treating human disease, with the view to taking it to clinical trials.

This study highlighted a new way in which tumour cells evade the immune response: by production of the ECM molecule tenascin-C, which can be used to switch TAM functionality. Further research is now needed to further dissect the heterogeneity within TAMs – that is to investigate what creates and defines ‘good’ vs ‘bad’ TAMs, in order to better understand which subtypes may be assisting cancers by protecting tumours. Through this, Kim hopes that tailored treatments can be created which target specific TAM subsets, rather all macrophages, which would potentially lead to safer and more effective anti-cancer drugs. Initial research through single cell sequencing by Kim and her team into this has shown that there are indeed many different types of TAMs, and they are now investigating the function and tractability of targeting each TAM subset.

About this research

Prof Kim Midwood is a Professor of Matrix Biology at the Kennedy Institute of Rheumatology. On top of the establishment of Matrix Immunology groups in Oxford and Imperial College London, she founded the BioTech company Nascient Ltd, which has developed anti–tenascin C antibodies that have applications in benefiting patients with rheumatoid arthritis.

Her research focuses on how changes in the extracellular matrix affect cellular signalling pathways in inflammatory diseases including arthritis, fibrosis and cancer.

This work was supported by grants from Worldwide Cancer Research, the Medical Research Council, Nascient Ltd., the Kennedy Trust for Rheumatology Research, the Austrian Science Fund, and the Institut National contre le Cancer.