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T-cell landscape mapping identifies new targets for pancreatic cancer immunotherapy

Pancreatic cancer has one of the worst prognoses of any cancer, with pancreatic ductal adenocarcinoma (PDAC) patients having an average survival rate of 7%.

T-cells (the lymphocytes that play a wide range of roles in shaping the body’s immune response to cancer) are known to be less active in pancreas tumours. So far, checkpoint therapy trials, a type of immune-therapy that targets T-cells and have curative properties on other cancer types, have had minimal effect on pancreatic cancer with a response rate of only 5-10%. Furthermore there has been no lasting impact on a patient’s survival chance and current approved checkpoint therapies are focused on only targeting only two T-cell checkpoints, known as PD-1 and CTLA4.

In order to better understand checkpoint treatment has had a minimal impact on pancreatic cancer, and how to improve their efficacy, there is a need to understand the specific sub-populations of T-cells that are involved in pancreatic cancer. Even though we know T-cells exist in the microenvironment of pancreatic cancer, not much is known about why they are less active. There is also a need to identify new checkpoint therapy targets, beyond the two currently used, so that new, more impactful drugs may be developed.

A new study from researchers in the PancrImmune network at the University of Oxford, has characterised the immune landscape, and specifically the different T-cells, in pancreatic cancer patients, in the hope of understanding the features to aid drug development and novel therapeutics for this disease. This is the first comprehensive characterisations of T-cells in primary human pancreatic ductal adenocarcinoma.

The team looked at 32,000 T-cells from 8 cancer patients, to see if there were any unique T-cell subtypes in the tumour microenvironment. First, this data confirmed that the microenvironment of pancreatic cancer is extremely suppressive and could be a major driver of poor prognosis. Secondly, they have also identified important genetic components of these T-cell subtypes that may be driving this immunosuppression, which could be potential targets for future immunotherapy drugs.

Specifically, their observations showed an activated regulatory T-cell population, which was characterized by a highly immunosuppressive state with high TIGIT, ICOS and CD39 gene expression. The exhausted CD8 T-cells had lower PD1 levels but high levels of TIGIT and tim3. As well as the presence of a significant senescent T-cell population – this is when cells have gone down an irreversible cell cycle arrest and are no longer responsive to antigen stimuli.

This means that new potential checkpoint immunotherapy avenues in TIGIT, ICOS, CD39 and Tim3, that target these populations, may have more potential to improving the prognosis of pancreatic cancer.

The next step in this research is to take the newly-identified immunotherapy target and begin clinical experiments using targeted immunotherapy drugs. This may eventually lead to clinical trials to test these drugs in patients.

Mapping the immune landscape in PDAC patients is a huge step in pancreatic cancer research, as PDAC tumours represent 50% of all pancreatic cancer diagnoses. So new targets identified in this study has the potential to generate novel drugs that could benefit a large range of patients.

About the study

This study was co-authored by researchers in the PancrImmune Network, including  Dr Shivan Sivakumar (Dept of Oncology), Dr Enas Abu-Shah (Kennedy Institute of Rheumatology, Prof Mark Middleton (Dept of Oncology), Dr Rachael Bashford-Rogers (Wellcome Trust Centre for Human Genomics),  Prof Michael Dustin (Kennedy Institute of Rheumatology), Mr Michael Silva (University Hospitals NHS foundations Trust) and Mr Zahir Soonawalla (University Hospitals NHS foundations Trust).

DeLIVER clinical research study underway as recruitment opens

DeLIVER is a five-year Cancer Research UK-funded research programme led by Professor Ellie Barnes (Nuffield Department of Medicine) that aims to detect liver cancer earlier. Liver cancer is the fastest rising cause of cancer death in the UK, with more than 5,000 deaths per year. To improve survival, it is crucial to diagnose liver cancer earlier, when current treatments are more likely to be successful. However, this is challenging because symptoms are vague and late-presenting, and are frequently masked by co-occurring liver disease, such as cirrhosis.

A major goal of the DeLIVER programme is to learn more about the biology of liver cancer development and to use this information to design more sensitive detection tests. Because many people being tested for liver cancer have the high-risk condition cirrhosis, these tests need to be specific enough to detect liver cancer on top of other changes in the liver caused by cirrhosis. In order to identify the defining characteristics of early liver cancer, researchers need to perform a detailed molecular analysis of tissue from tumours and the background liver in people with liver cancer and cirrhosis and compare this to liver tissue from people with cirrhosis alone.

The DELPHI (Deep Liver Phenotyping and Immunology) study will recruit 100 participants at Oxford University Hospitals NHS Trust. 80 of these recruited participants will have cirrhosis (caused by hepatitis virus B or C, fatty liver disease or alcohol) and 20-30 participants will have liver cancer in addition to cirrhosis. After giving consent, the participants will undergo fine-needle aspiration to collect tissue from the liver. This is a safe technique established in Oxford as one of only a few centres in the UK. Blood samples will also be taken.

Cancer Research UK Clinical Research Fellow Dr Rory Peters is leading the study. He said,

“We are very pleased to have started the recruitment for the DELPHI study. The in-depth analysis of samples from the DELPHI participants will be critical for increasing our understanding of how liver cancer develops and will give insights into how this cancer can be detected earlier.”

The researchers will look at individual cells to understand the cellular make-up of the tumour and surrounding tissue, including infiltrating immune cells, and how this may influence cancer development. By comparing the tissue from participants with and without cancer, they will also look for changes in protein or metabolite levels and alterations in the levels of chemical modification of DNA by methylation using the TAPS assay developed in Oxford by Dr Chunxiao Song. They will investigate whether the changes that they observe from the tissue analysis can also be detected in the blood, which would provide evidence that a blood-based assay could be developed as a less invasive diagnostic test.

Professor Ellie Barnes, Chief Investigator for DeLIVER said,

“The DELPHI study is one of three clinical projects within the DeLIVER programme. Together, these studies will inform us which of our diagnostic technologies perform best at detecting liver cancer at the earliest stages. We hope this work will lead to a step-change in earlier liver cancer diagnosis and improved patient survival.”

 

Read more about the DeLIVER programme in the OxCODE liver cancer early detection research showcase.

Prof Andi Roy receives new award for immune-cell research

Co-funded by Cancer Research UK and Children with Cancer UK, Andi is one of 5 to receive £1 million each to investigate children’s and young people’s cancers.

Improving immunotherapy through epigenetics

Immunotherapy has shown remarkable efficacy against a range of cancers. One approach, termed immune checkpoint blockade therapy, blocks an inhibitory immune receptor called PD-1 to take the brakes off the immune system and allow it to kill cancer cells. However, despite this success, anti-PD-1 therapy is ineffective in the majority of cancer patients.

Research is underway to discover strategies that can overcome tumour resistance to immunotherapy. A promising avenue for further investigation is the manipulation of epigenetic regulators. Epigenetic regulators influence the expression of genes without changing the underlying DNA sequence. They can dampen the response of the immune system and their inhibition has been shown to enhance the response to anti-PD-1 treatment. However, because epigenetic regulators are involved in several aspects of the anti-tumour immune response, inhibiting them can result in potentially opposing effects, with the result of little or no overall benefit.

In this paper published in the journal Cancer Discovery, Professor Yang Shi and his laboratory explore the opposing effects of inhibiting one such epigenetic regulator, LSD1. Using mouse and tumour cell models, they show that when LSD1 is repressed, there is a greater immune cell infiltration into the tumour but this is counteracted by the increased production of a cell regulatory protein called TGF-β that suppresses the ability of these infiltrating immune cells to kill cancer cells.

To tackle these conflicting effects, the team experimentally depleted both LSD1 and TGF-β during anti-PD-1 therapy and demonstrated a significant increase in immune cell infiltration, cytotoxicity and cancer cell killing. This combination treatment led to eradication of these previously resistant tumours and long-lasting protection from tumour re-challenge, making it a promising future strategy for increasing the efficacy of this important class of cancer treatment.

Christina Ye awarded CRUK pre-doctoral fellowship

Immune related toxicity is a common side effect of treatment with Immune Checkpoint Blockers for cancer – but the degree to which the development of these side effects is related to overall oncological outcome is unclear. As an Academic Foundation Programme Trainee within OUCAGS (https://www.oucags.ox.ac.uk), I had a four month block of time to work in a lab to gain experience of research. I worked with Dr Benjamin Fairfax’s group in the WIMM/Department of Oncology to explore the relationship between immune toxicity and clinical outcomes. Working with other members of the group, and Dr Anna-Olsson Brown in Liverpool, we found that patients who developed immune related toxicity appeared to have better long-term clinical outcomes including overall survival. Indeed, we found the development of toxicity was a key predictor of the cancer responding to treatment. This work is currently in-press in the British Journal of Cancer.

This period of time in the lab stimulated my interest in research and helped in my decision to apply for an Academic Clinical Fellowship in Dermatology. I was successful in this and I have a further nine months of protected research built into my training this year, which I again plan to spend working in Ben’s group. As a trainee dermatologist I am particularly intrigued by the rash patients frequently develop when they first receive immunotherapy. There is evidence to suggest that another side effect of immunotherapy, colitis, is secondary to the activation of resident memory T cells. Conversely, when you look at the gene expression in CD8 T cells after treatment with checkpoint blockers you can see up-regulation of genes involved in skin trafficking. I will explore whether this rash is indicative of T cell trafficking to the skin, or activation of resident memory T cells, or something completely separate.

Cancer Research UK awards biannual pre-doctoral research bursaries, aimed at providing ‘short term funding to allow clinicians and other health professionals to get involved in research projects early in their career’. Ben encouraged me to apply to this CRUK scheme to further explore the mechanistic basis of the rash in immunotherapy and I am very grateful to have been awarded this funding. Personally I am hoping to gain training in immunological techniques and bioinformatic analysis during this period, and I hope the results we generate will provide further insights into the cells cancer immunotherapy affects and how it works.

What we can learn from cancer survivors

Understanding how an individual survives cancer, and why they respond well to therapy, can be vital in identifying new therapeutic targets. A new project seeks to see why some advanced pancreatic cancer patients overcome the odds and respond positively to treatment.

Therapeutic potential for breast cancer found in the matrix

Work currently underway in the laboratory of Prof Kim Midwood is investigating the therapeutic anti-cancer potential of tenascin-C, a molecule found in the extracellular matrix of breast cancer

Researchers discover mutation that determines treatment efficiency

Weatherall Institute of Molecular Medicine researchers have recently discovered why a class of cancer drugs is beneficial only in a subset of patients

Mapping the T-cell landscape of pancreatic cancer

Through analysis of T-cell populations, researchers Drs Enas Abu-Shah & Shivan Sivakumar identify novel therapeutic opportunities in pancreatic cancer patients

Dr Eileen Parkes joins Oxford Cancer

Eileen brings research into the body’s innate immune response to cancer and how we can harness these pathways to develop novel clinical treatments