PhD Perspectives: Understanding how the immune system influences liver cancer

My name is Devnandan Chatterjee, and I am a final year PhD student at the University of Birmingham funded by the NIHR Biomedical Research Centre (BRC): Birmingham.

My research focuses on understanding how primary liver cancer – known as hepatocellular carcinoma (HCC) – and the environment in which it develops affect immune cells that normally help the body fight infections and disease. By investigating these interactions, I aim to identify new therapeutic approaches for treating HCC.

From London to Birmingham: my research journey

As a Gastroenterology specialist trainee doctor, I have taken time out of my medical training programme in London to pursue a PhD before continuing my pathway towards becoming a Hepatology consultant. The opportunities available through the NIHR BRC: Birmingham provided a unique environment for this work and inspired my move from London to Birmingham to undertake my PhD.

Throughout my medical training, I have developed a strong interest in improving the care of patients with liver disease and its complications. To pursue this further, I became involved in a range of research activities alongside clinical training. HCC is a common complication of liver disease, and survival rates remain poor. As a result, I have been keen to understand why HCC develops, which factors drive its progression, and how we can develop more effective treatments.

Understanding the links between liver disease, cancer and the immune system

HCC is a leading cause of cancer-related deaths in the UK and worldwide. Current immunotherapy treatments, which help the body’s immune system to recognise and fight cancer, have shown promise – but are effective only in a minority of patients with HCC.

Nearly all HCC cases develop in context of scarring, known as cirrhosis, resulting from underlying liver disease. Macrophages, a type of immunecells that destroy bacteria and other harmful organisms, accumulate within the scarred liver tissue; and rather than killing the cancer cells, they can help the HCC to grow. However, the ways in which the cirrhotic liver environment changes macrophage behaviour remains poorly understood and needs further research.

My research seeks to address this question using novel human-derived liver models and advanced technologies to map the cellular and molecular landscape of liver cancer. These approaches include cutting-edge genetic and protein profiling techniques that allow us to better understand how the liver environment shapes immune cell function.

Importantly, macrophages are highly adaptable cells whose function can be reprogrammed. This makes them attractive targets for effective new treatments. By identifying the factors that influence macrophage behaviour in HCC, my work aims to uncover barriers to current treatments and support the development of more effective therapies, ultimately aiming to improve the outcomes for patients with HCC.

Why this research matters

Rates of HCC are rising and long-term survival remains poor, with 5-year survival rates being 10-18% despite advances in treatment. We urgently need to improve our understanding of why patients with liver disease develop HCC and how we can better treat it.

The rates of liver cirrhosis are also increasing significantly, something I have witnessed firsthand in clinical practice. As a result, growing numbers of patients are at risk of developing liver cancer. By understanding the characteristics of liver environments that are most susceptible to HCC – and how these environments influence immune cells that may drive tumour development – we can identify new therapeutic targets and improve patient outcomes.

Building a picture of the liver cancer environment

During my PhD, I have developed and applied a range of experimental techniques. Through the BRC: Birmingham infrastructure, we have access to human liver samples generously donated by patients at the Queen Elizabeth hospital. Using these samples, I have developed novel human-derived models of the liver’s supporting protein scaffold, known as the extracellular matrix, and have used them to study how different liver environments influence macrophage behaviour.

The advanced imaging facilities and analytical technologies available at the University of Birmingham have enabled me to observe directly how macrophages interact with and adapt to these human-derived scaffolds. Working with the Next Generation Therapies BRC research theme, I have also been able to measure the stiffness of the liver tissue non-invasively, allowing me to characterise its physical properties without affecting cell growth.

By combining information about the physical properties (stiffness) and chemical properties (protein make-up), I will be able to gain greater understanding of how the liver environment contributes to HCC development.

In addition, I have used spatial transcriptomics and spatial proteomics, groundbreaking technologies that allow us to map the location of genes and proteins within tissue samples. Applying these techniques to samples which include HCC and the surrounding liver tissue will enable me to compare findings directly with my experimental models, to help identify potential new treatment targets.

Connecting discoveries in the lab to patient care

Alongside my research, I participate in a weekly HCC clinic where I care for patients living with liver cancer. This close connection between clinical practice and laboratory research allows me to link scientific discoveries directly to potential patient benefits.

One of the most exciting discoveries during my PhD has been developing a new way to create scaffolds from human tissue and demonstrating that they can influence how immune cells behave. I have shown that macrophages cultured in healthy and cirrhotic liver scaffolds respond differently, demonstrating that the surrounding environment plays a critical role in shaping their function. Importantly, the cirrhotic liver extracellular matrix alone appears capable of driving macrophages towards states that are known to promote HCC development.

I am also excited by the opportunity to work with cutting-edge technologies and to integrate approaches from different research disciplines – learning and combining these techniques to provide fresh insights into why HCC develops and helping identify new opportunities for treatment. The potential discoveries that lie ahead are particularly exciting.

My experience as a BRC PhD student

This fellowship has provided me with dedicated time to pursue research interests developed through my clinical practice. It has also given me access to an outstanding research infrastructure, enabling me to undertake an ambitious project while developing a broad range of research skills.

Beyond funding my PhD, the BRC has provided the platform and support needed to enable me to secure additional research funding, including grants from NIHR, Cancer Research UK, Guts-UK and BAPEN. It has allowed me to remain actively involved in clinical research while undertaking laboratory-based work.

The programme has offered numerous opportunities for professional development, including research training courses, workshops, conference attendance and presentations, and interdisciplinary networking. I have also had the opportunity to lead clinical research projects from conception through to study delivery. All these experiences allowed me to develop further and have provided me with valuable insight into a future career as a clinical academic.

Balancing clinical commitments alongside laboratory research has undoubtedly been challenging at times. However, the ability to continue clinical practice alongside my PhD, supported by the BRC, has been invaluable for my professional development. It has enabled me to gain experience in a tertiary liver transplant centre and managed patients with HCC in a regional specialist centre, complementing my research training with clinical experience.

Looking ahead

I hope that the insights generated through this research will contribute to the development of new treatment strategies for patients with HCC. Furthermore, the interdisciplinary approaches and novel techniques developed during this project may help drive future collaborations and create innovative ways to study the HCC tumour environment.

Ultimately, by improving our understanding of how liver disease shapes the immune system and influences cancer development, this research has the potential to identify new therapeutic targets and improve outcomes for patients with liver cancer.