The tumour microenvironment in primary brain cancers

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Published: 11 May 2018
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Dr Johanna Joyce - Ludwig Institute for Cancer Research and the University of Lausanne, Lausanne, Switzerland

Dr Joyce talks to ecancer at the Cancer Research UK Brain Tumour Conference 2018 in London about the importance of understanding the tumour microenvironment in brain malignancies.

I was talking about the importance of the tumour microenvironment in the context of brain malignancies, mostly focussing on primary brain cancers but we also believe that the tumour microenvironment is very important for understanding and targeting brain metastases as well.

We look at it in many other contexts as well. We have, over the years, looked at the importance, for example, of a cell type we believe to be very important – tumour associated macrophages in pancreatic cancer, in breast cancer and now in brain malignancies. We think that there’s actually a lot to be learned from comparing and contrasting the functions of those cells but other cells in the microenvironment, depending on the organ, depending on the underlying malignancy that we’re investigating.

What are you looking at, specifically in brain tumours?

We are looking at the potential roles for tumour associated macrophages. Those include resident microglia that can get co-opted in the context of brain cancer progression, in the context of metastasis, but also cells that are recruited from the periphery. So particularly as gliomas, for example, progress, develop, become more malignant there’s an increase in the abundance of macrophages that are recruited from the periphery. So potentially important, we still don’t know if the resident microglia and the recruited macrophages have the same functions or potentially have some opposing functions. So that’s obviously important to understand in the context of targeting those cells therapeutically.

Has there been much reporting of data from this so far?

No, there has been quite some reporting on this and there are a number of clinical trials that are ongoing using various different agents to target macrophages in many cancer types, including in gliomas. So the trial data, we’re still waiting to see what the final results are from that but it’s certainly a rapidly moving field, yes.

What targeting agents have been used in gliomas?

For targeting macrophages it has mostly been inhibitors of a key signalling pathway important for those cells, colony stimulating factor 1 receptor pathway or CSF1R. There are a number of small molecule inhibitors but there are also antibodies that target that receptor that have been tested in various different clinical contexts including, again, in gliomas.
So, again, immunotherapies are now in clinical trials for glioma patients. Results so far, at least with monotherapies, are certainly not as striking as what has been observed for the kind of successes of melanoma and lung cancer, for example. So, again as a community, it’s really important for us to understand what are the ideal combinations that one may want to test with those immune therapies. So what we certainly believe is targeting immune suppression within the brain microenvironment, including in the context of gliomas, is going to be key to essentially unleash the ability of T-cells to then be activated to kill the tumour cells. Myeloid cells, including tumour associated macrophages and microglia, are really a key immune suppressive cell type within the brain. So we think it’s really important to consider approaches to target them in conjunction with immunotherapies.

The take-home messages are that it’s really important to understand the complexity of the cancers that we study if we are to have any success in therapeutically targeting those. Often the focus historically has been, and this applies to many aspects of cancer research, to just focus on genetic genomic changes in the cancer cells themselves with maybe minimal appreciation for the importance of immune cells, the blood vasculature, the lymphatic vasculature and so on. We know that they have profound effects in terms of cancer initiation, progression, metastasis, therapeutic response, and so we think it’s really key to understand and investigate cancers in their native microenvironment. But it’s also becoming increasingly important to think about how systemically cancer alters the immune system, for example, and how that can impact again on cancer progression and also therapeutic response.

So going forward we take the lessons that we’ve learned from understanding the local tumour microenvironment and apply that at a systemic level as well. That’s going to be key for many of the aspects of what we’ve been speaking about during this conference.