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A study from the Fairfax lab provides new insight into the factors that determine patient response to Immune Checkpoint Blockers, a common immunotherapy treatment for melanoma.

We see a single T Lymphocyte on a black background. This is a colorized scanning electron micrograph image showing the 3D shape of the cell. © NIAID

In the study, published in the journal Science Immunology, researchers from the Fairfax lab in the MRC WIMM and Department of Oncology, identified specific aspects of the immune system that are important in determining the response to Immune Checkpoint Blocker treatment for melanoma.

The work, led by DPhil students Robert Watson (Wellcome Clinical Research Fellow), and Orion Tong (Clarendon Scholar), used single-cell sequencing to determine which components of the immune response are most impacted by Checkpoint Blockers.

This work found crucial differences in subsets of CD8+ T cells. The greatest magnitude of gene expression change following treatment occurred in a specific group called the ‘Effector Cell’ subset, but crucially, the size of the T cell ‘clone’ was critical in determining the response.

CD8+ T cells are crucial to the anti-cancer response to immunotherapy and carry specific receptors (T cell receptors) that allow recognition of their targets. CD8 T cells that carry the same receptor are known as a clone -  there are millions of T cell clones within us all, and the Fairfax group has previously found the number of enlarged CD8 T cell clones melanoma patients have in their blood after starting treatment is associated with long-term clinical response.

Here the research team used single-cell sequencing to identify what is special about these large clones, to find that they are most sensitive to immunotherapy and express genes that are particularly toxic to cancer cells. Interestingly, they are more likely to carry receptors previously found on T cells within melanomas from other groups.

The researchers also found that after treatment, more cytotoxic cells persisted for longer in the peripheral blood. Building on those findings, the team found that patients who have more large clones and higher cytotoxicity pre-treatment were more likely to live for longer without the cancer progressing.

The findings have important implications for patient care, as they demonstrate that information derived from a small peripheral blood sample can closely correlate with future clinical outcomes. The results also indicate that the pre-existing immune state is crucial in determining response.

By identifying the factors that determine response to immunotherapy we will be better able to understand why some patients do not benefit – our work suggests that the pre-treatment immune response to melanoma is really crucial. You could therefore reason that future therapies will need to enhance the ability of the body to detect melanoma – potentially by improving antigen presentation
Dr Robert Watson

 What are immune checkpoint blockers?

Immune checkpoint blockers are the most commonly prescribed immunotherapy for cancer. While first used in metastatic melanoma, they are now licensed for use to treat many cancers.

A combination of more than one type of immunotherapy drug tends to give better long-term outcomes for melanoma patients, but it often also has more side-effects. So knowing whether a patient will respond well to immunotherapy could be used to rationally stratify treatments in future – targeting the combination treatment at those with higher risks.

Predicting future outcomes

It’s usually thought that you need to look closely at cancer cells themselves to understand the immune response to cancer. But features of peripheral blood cells can also give insights into body’s response to cancer. Oxford researchers have been studying changes across large cohorts of patients – allowing them to detect important prognostic factors which might not be seen in smaller immunological assessments.

By analysing a large dataset of samples from 131 melanoma patients, the research team spotted that, even before treatment, patients who have long-term control of their cancer with treatment have either more cytotoxic CD8+ T cells or larger clones in their blood. This indicates that immunotherapy is working on the body’s pre-existing response to the cancer- in line with the findings of other groups.

Senior study author Dr Benjamin Fairfax, who is an Associate Professor at the Department of Oncology and a Consultant Medical Oncologist, said: “Whilst molecular features of melanomas have long been shown to inform us as to sensitivity to immunotherapy, it has been much harder to identify features in patient’s blood that can give similar insights.

Using blood is obviously much easier in terms of sampling over time and so naturally would be beneficial. Further efforts to improve patient outcomes should focus on trying to induce this response across all patients.”

 

I am really excited to take this principle further and identify expression profiles of other peripheral immune cells that may similarly further our understanding of how an individual’s immune system means they are going to benefit from cancer immunotherapy.
 - Orion Tong

Dr Miranda Payne, Consultant Medical Oncologist and Lead Melanoma clinician in Oxford said “I am very excited by the results of this work which is a reflection of the generous involvement of melanoma patients in our clinics. They show that, to a certain extent, we can predict long-term clinical benefit of immunotherapy for melanoma from patient blood samples.

This is important because it suggests we may be able to use such blood markers in the clinical setting to further stratify our treatments available for patients with the aim of minimising side-effects and improving patient outcomes. This would need to be based on further clinical trials, but this basic science is crucial to permitting these.”

Professor Mark Middleton, Head of the Department of Oncology, and a co-author on the work said: “Working out which patients will benefit from immunotherapy before they receive it is going to be important as the number of drugs in the clinic increases. It is likely that for some patients whose cancers carry specific mutations immunotherapy may not be the best approach, whereas for others, adding in additional treatments may be helpful. There have been tremendous advances in our ability to look at immune responses and our work adds to these. It is typical of the cutting-edge, patient-facing studies we are performing in Oxford in the Department of Oncology with support from the Oxford BRC.”

The major funders for the study were the Wellcome Trust, who fund Dr Fairfax and his lab and Dr Watson’s DPhil; the Oxford Biomedical Research Centre, who have supported patient recruitment and sample collection; and CRUK, who previously awarded a pre-doctoral bursary to Dr Watson which paid for the single-cell sequencing crucial for this work.

See the published paper for a full list of funders.

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