High-quality neoantigens are immunoedited in long-term survivors of pancreatic cancer

Prof Marta Luksza - Tisch Cancer Institute, New York, USA

In this work we have studied the evolution of cancer in pancreatic cancer survivors. We wanted to know if there are any signatures of selection imposed by the immune system that could be seen during this evolution. So we have collected the data, along with collaborators from Memorial Sloan Kettering and Johns Hopkins, have collected samples from pancreatic cancer survivors over ten years. So we have primary tumours and metastatic tumours and we have shown that in the long-term survivors the activity of the immune system really has a huge impact on how the metastatic tumours look. So we knew what are the clones and which mutations get to be edited and we also developed a mathematical model that can be used to, to some extent, predict the evolution of metastases.

What was the methodology used in your study?

Our methodology was based on two things: one was a mathematical model that we actually have previously developed that quantifies immunogenicity or quality of neoantigens in cancer. So neoantigens are mutated peptides in tumours, these are just parts of proteins that contain mutations. Due to those neoantigens, those mutated peptides, the tumours or the cancer cells may become visible to the immune system because they are presented and then can, by this MHC class 1 mechanism, be recognised by the immune cells.

We have previously developed a mathematical model that can quantify which mutations can generate highly immunogenic peptides, so such peptides that are well recognised by the immune system. Previously we have shown that we could predict which patients would live longer because of this high immunogenicity of their tumours and increased activity of the immune system. Now we have used this to study this longitudinal data with tumour samples over many years to see how this immunogenicity can affect the evolution.

What were the key results of your study?

The key result was really, basically, the fact that we were able to show that the immune system has really high impact on the composition of metastatic tumours of those pancreatic cancer patients that are quite rare who lived over five years, up to ten years now and some of them are still alive. We have contrasted the composition of the tumours with a group of short-term survivors who did not show this pattern so whose immune systems were not as activated as in these long-term survivors. So we have really shown in human cancer that the immune system can have high impact and can be activated even without immunotherapy. On its own there can be an indigenous response of the immune system and that, indeed, it can affect the evolution.

How might these results impact the research and treatment of cancer?

First of all this is quite a general, basic science result where we have shown that this activity of the immune system is an important factor for predicting the evolution. But, of course, once we have discovered such a key element of the mechanism that affects the evolution we can use it later for doing predictions and for planning better the therapies and the course of treatment. Because any method or methodology that allows us to predict into the future and in this case it allows us to infer which of the clones or mutations are likely to be eliminated from the tumour on its own, this can help us to plan which other mutations should be targeted by treatment. So it just gives us a very basic insight into the course of evolution and plan. Hopefully in the future it can help us to plan treatments.

It’s an interesting result for pancreatic cancer because pancreatic cancer is believed to be a tumour that is not… it’s not the first type of tumour that is thought of in the context of immune system activity and immunotherapies. So it so far has been believed that in this type of tumour the immune system is not active and there is not much room for immunotherapies because it’s not highly mutated. So this is one of the novel results here is that we’re showing that there is some indigenous response of the immune system which could be further increased by the application of immunotherapies.