3rd Immunotherapy of Cancer Conference (ITOC3)
Hypoxia and its impact on the immune system
Dr Luigi Varesio - Giannina Gaslini Institute, Genova, Italy
We deal mostly with neuroblastoma, that is one of the most frequent solid paediatric cancers and for which the prognosis is not very good, about 50% of the high risk patients die and for the time being we are all looking for new approaches, including immunotherapy based approaches for treating this disease.
Could you tell us about your research in hypoxia affecting the microenvironment?
Sure. The idea behind it is that if you want to deal with a tumour you have to deal with the whole tumour mass which is composed by many cellular types, not just tumour cells but also leucocytes that infiltrate the tumour - macrophages, dendritic cells, eosinophils, all kinds of leucocytes. And then also you have to take care of the stroma cells, the vessels, so there is a complex mass. Within a tumour mass you have signals, very important signals, and one of these is hypoxia, namely there is a low oxygen tension which is very important because every cell in the tumour mass has to feel this low oxygen sensor. There are no receptors so there are sensors in each cell and each cell responds to hypoxia. The response to hypoxia makes these hypoxic patches, areas, and you can find them within the tumour mass, areas highly hypoxic and less hypoxic. Now hypoxia is associated with resistance to drug treatment and also improves or increases metastatic spread so it’s a negative factor for the tumour. In fact, we can see in neuroblastoma children the higher the tumour hypoxia the worse is the prognosis. So in one way we have to deal with it and we have to deal with the situation in which you have non-hypoxic tumour cells and hypoxic tumour cells, non-hypoxic lymphocytes and hypoxic lymphocytes that coexist in different compartments within the tumour mass. Unfortunately the treatment for those hypoxic tumour cells and non-hypoxic tumour cells has to be different because one cell is sensitive and the other is resistant to treatment. Therefore it is complex and there are new promising avenues. On the one hand we can take advantage of the fact that the macrophages, dendritic cells, the immune cells travel from hypoxic areas to non-hypoxic and vice versa. So hypoxia is not a static situation, it’s a dynamic situation and we can take advantage of that to carry or to deliver immune reactive cells from one place to the next. Another is to develop drugs; there are now drugs being tested which are active only on the hypoxic condition. So one idea would be to treat sequentially the patients with drugs that are mostly effective under non-hypoxic conditions followed by drugs which would be activated only under hypoxic conditions thereby trying to get rid of the remaining hypoxic niches.
So this is basically the leading idea. The problem with that, of course, is that you cannot really biopsy kids sequentially so you have to find out some way, somehow, to figure out whether we are dealing with hypoxic response, whether the kids respond to therapy. This is the last approach we have taken is to monitor exosomes. Exosomes are small vesicles released by the tumour that are floated into the blood stream and you can look at these exosomes. The content of the exosome reflects the content of the cells from which they come from and notably there are molecules like small RNA, very stable, called microRNA, that can be used as a biomarker of the biology of the tumour. This is what we have been doing in the neuroblastoma; other groups are doing similar things in other kinds of cancer, big cancer. There is good indication that going back to the hypoxia problem we can derive from these exosomes some signature, some group of microRNA, that will indicate whether or not there is a hypoxic area or there is a large hypoxic area in the tumour and whether or not drugs that should affect the hypoxic area of the tumour are actually working functionally.
What is the clinical applicability?
I think that the exosome kind of research has the highest applicability because we can do more work on it. It’s a non-invasive way of getting information on the tumour. So even in terms of getting a sample from the patients all it takes is to obtain one or two mls of blood and it’s something doable, even if we are dealing with small kids. So it’s something that can be done ethically and can be done on a sequential basis so we can follow the response of the patient on time along the timeline.
What do you see on the horizon in terms of drug development?
As you may or may not know it is difficult to experiment new drugs in kids because, fortunately for the kids and unfortunately for research, these tumours are very rare and companies are not that interested in experimenting drugs on a small population of patients. Therefore, the future of this will depend a lot on what is going on with other kinds of tumours. Eventually we can utilise in the paediatric environment tumours that were developed for adult patients or for different… And this is a complication because neuroblastoma is only a paediatric tumour so we have to rely on drugs that were derived for melanoma, derived for other kinds of cancer. But nevertheless the problem of hypoxia as a risk factor is not unique to neuroblastoma, it is something that occurs in breast cancer, prostate cancer, so it is likely that the research in which you try to deal with the hypoxic tumour cells or the hypoxic part of the tumour may progress and drugs be developed in other kinds of tumours that could be applicable for neuroblastoma.