NUI Galway study discovers novel approach to tackle bowel cancer

Scientists from the Regenerative Medicine Institute in the School of Medicine at NUI Galway, in collaboration with Queen’s University Belfast, have found a new function for normal cells, called stromal cells, within tumours that point the way in better understaning and preciction of response to immunotherapy. The study has been published in the internationally renowned journal, Cancer Immunology Research.

Colon cancer is one of the most common cancers affecting both men and women in Ireland. Current treatments can combine radiotherapy, surgery and chemotherapy, but response rates in late stage disease can be disappointing. To date, therapeutic developments to tackle the problem of bowel cancer spreading to other parts of the body have had limited success and new methods are urgently needed to improve survival for patients.

Immunotherapy is a new form of treatment where different medicines or cells can re-engineer a patient’s immune system to better target cancer cells for destruction. In some forms of cancer, immunotherapy has led to marked improvements in patient outcome for particular patients. Cancer cells can express substances to cloak themselves from attack from the immune system. These protein substances are a usually a vital part of regulating why the normal immune system doesn’t attack all cells but these normal protective mechanisms can be hijacked in tumours protecting the cancer from damage. Immunotherapy attempts to overcome these hijacked systems and allow the immune system to kill cancer cells.

While these treatments hold potential for improving the treatment of therapy-resistant cancers with potentially fewer side effects, in general colon cancers respond poorly. The research findings indicate that normal stromal cells which surround a tumour could potentially contribute to that protective cloaking from the immune system and simultaneously drive the dangerous spread of these cells to other parts of the body.

By combining laboratory models with patient samples, the research team, led by Dr Aideen Ryan in the School of Medicine at NUI Galway, has shown for the first time that PD-L1 (one of the protein substances involved in cloaking cells and tumours from the immune system ), is expressed not only on the tumour cells but also on the normal stromal cells within the tumour. The expression of PD-L1 by these stromal cells essentially “switches off” the killing activities of the immune system, even before it reaches the cancer cells. The expression of stromal cell PD-L1 is even higher, in certain conditions such as inflammation, which can occur within the tumour. The combination of the cloaking processes in the stromal cells and tumour reduces the chances of the immune system killing the cancer cells and can drive these cells to spread and metastasise.

Using colon cancer cells and either normal or tumour exposed stromal cells, the research team found that blocking PD-L1 signalling increased the production of immune activating signals and increased the number of tumour killing T cells. Furthermore, in a pre-clinical model of colon cancer, anti-PD-1 therapy reversed the ability of tumours to grow and metastasize, increasing the effectiveness of anti-tumor T cells. In human samples, PD-L1 expression was observed to be higher in stromal cells exposed to human tumours than in the tumour cells themselves. Additionally, in tissue from two small groups of colon cancer patients, they confirmed higher expression of PD-L1 in the stromal cells compared to the colon cancer cells. This is an important finding as patients are currently chosen to receive this therapy based only on if the tumour cells express PD-L1 or not.

Lead author of the study, Dr Aideen Ryan from the School of Medicine at NUI Galway, said this study proposes a change in thinking. Until now, if we wanted to know whether a colon cancer patient was likely to respond to immunotherapy, we would look at their tumour cells. This study has shown us that instead of just looking at the tumour cells we need to look at the environment surrounding the tumour as well. Our findings address previous observations of positive anti-tumor responses to PD-1 immunotherapy in patients whose tumours have been deemed PD-L1 negative. Our findings provide a clear motivation to assess stromal cell PD-L1 expression in order to better choose patients for immunotherapy.”

“Our future research will investigate the exact ways by which the colon cancer cells interact with and dictate the function of noraml stroma within tumours to prevent recognition by immune cells. Understanding exactly how this happens may help to discover new ways in which we can prevent this, and enhance responses to new immune based therapy,” added Dr Ryan.

Dr Robert O’Connor, Head of Research at Irish Cancer Society, said that this important study illustrates the extent of cutting-edge cancer research being undertaken by hugely talented scientists across Ireland.

“The findings by Dr Ryan and her colleagues are significant because they may point the way to much needed new applications of immune-based treatments for bowel and possibly other forms of cancer. Such findings are only made possible through many years of investment in high calibre researchers like Dr Ryan and her colleagues and we need continued support to generate further advances in our improving cancer outcome.

The study was supported by Science Foundation Ireland, Irish Cancer Society, Irish Research Council, and Galway University Foundation.

To read the full study in Cancer Immunology Research, visit: http://cancerimmunolres.aacrjournals.org/

content/early/2018/09/18/

2326-6066.CIR-17-0443

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