The great escape artist – how tracking co-evolution could improve immunotherapy

Therapies designed to reinvigorate the immune system to clear tumours have shown real promise. This is good news for patient impact, but it has also demonstrated that the immune system can recognise and mount a response against tumours.

It also highlights that tumours actively induce an immunosuppressive state where CD8 T cells become “exhausted” and are no longer able to control tumour growth.

Alongside this, there has of course been incredibly exciting results instrumental in treating aggressive cancer using immune checkpoint blockade (ICB), which blocks receptors in pathways that attenuate T cell activation. However, for metastatic melanoma, only 3 out of 10 patients who receive ICB will survive their cancer for 5 years. As such, it’s vital that we improve our understanding of the mechanisms leading to tumour resistance.

The co-evolutionary landscape

Tumour cells divide and mutate quickly. If a tumour cell gains a mutation which helps it to escape detection, it will survive long enough to divide into more cells carrying this adaptive mutation. These cells become dominant and no longer controlled by the immune system, which might lead to tumour outgrowth and decreased patient survival.

By profoundly affecting each other, cancer cells and T cells co-evolve into a landscape where pressure from T cells will determine what the next escaping tumour cells will be and, inturn, tumour cells alter immune composition and fitness.

T cells produce the cytokine interferon-gamma (IFN-gamma) which inhibits cancer growth by preventing tumour cells from dividing and by supporting other T cells to recognise and kill them. But cancer cells can evolve to lose sensitivity to IFN-gamma and proliferate despite its presence. We know that mutations leading to loss of sensitivity to IFN-gamma often emerge following ICB. This creates a selective pressure allowing those mutated tumour clones to emerge, resulting in their uncontrolled proliferation.

So, by studying the spatial and temporal processes of immune escape I think it’ll  help us understand why and when ICB works and, crucially, when it doesn’t, using IFN-gamma-dependent escape as a model. This could lead to better targets for treatment aimed at a particular window of cancer evolution.

A question of  space and time

We often rely on a few biopsies to monitor tumour mutations in patients undergoing ICB. This makes it challenging to infer when a mutation occurred relative to the timing of ICB, and whether it matters for the efficacy of the treatment.

In cases of escape, this snapshot does not tell us about what happened before or what will happen after – nor does it allow us to consider which immune response was already present at the time of immune escape.

Whether –  and how – certain mutations can trigger immune remodelling as they appear and take over is therefore mostly unknown.

Spatial omic technologies have enabled studies into the organisation of the immune landscape and tumour clone heterogeneity. Studying the spatial immune landscape is important, as there is a growing understanding that the location of T cells within the tumour micro-environment has a profound effect on their capacity to target and kill tumours. T cell exclusion from the centre of the tumour, for example, is often correlated with a poor response to immunotherapy.

Studies on  tumour spatial organisation also describe a highly heterogeneous clonal  landscape. However, it’s unknown how the spatially-organised immune and tumoural microenvironments are related to create these holistic effects on treatment outcomes.

Studying immune and cancer co-evolution in space and time is critical when we consider that mutations affecting response to IFN-gamma do not always lead to immune escape and tumour growth, and that we don’t know why. By doing so, we may uncover a window of opportunity when cancer cells are most targetable by immunotherapies, even when they are trying to escape the immune system.

How to crack the issue

My group has developed a system to study the interaction between tumour and immune cells over both space and time.

We engineered escape mutants that harbour fluorescent labels, allowing us to track them in space and time. In addition, those mutations are inducible, meaning we can decide when they appear. Funded by the CRUK, we are using this system to observe immune evolution and tumour escape while it happens.

Using spatial omics and immunological assays, we are specifically investigating how the immune system co-evolves with IFN-gamma-dependent escape. We hope to understand whether there is a sweet spot where this newly adapted immune system might be less dysfunctional and thereby more amenable to respond to immunotherapy.

In addition, we want to know whether the presence of specific mutations in the IFN-gamma pathway and immune adaptation before ICB treatment interferes with the efficacy of ICB. This will improve our understanding of the relationship between co-evolution and current immunotherapies.

I am really hopeful that it offers new strategies to remodel the immune landscape through novel immunotherapy.