Exploring the role of T cells in the immune surveillance of early renal cancer

Context: The immune system is important at defending the body against cancer. When the immune system does not work as it should, cancer is more likely to occur.
Cancer is able to trick the immune system's defence. When this happens, cancer grows and can spread to other body parts. We still do not know what happens in the immune system in the first stages of cancer growth.
We have never been better at diagnosing kidney cancer early. Now, up to half of diagnosed kidney cancer cases are in early stages (i.e. small tumour in the kidney that hasn't spread to other body parts). We do not know why some early kidney cancers grow and spread through the body but others do not. Knowing why this difference exists can help inform how patients are treated and what the best course of treatment might be.

Aims and objectives: The main goal of this study is to understand the role of the immune cells in early kidney cancer growth. There are hints that a specific type of immune system cell, called T cell, plays an important role in the way cancer and the immune system work. I will be looking at these T cells. I will use tumour and blood samples donated by patients, and obtain the T cells. I will study how many T cells are in the tumour, what they look like, and how they work.
The second goal is to study how kidney cancer metabolism (i.e. the food it uses to grow) affects the way T cells work. Cancer cells use the nutrients (i.e. food) available around them. This leads to T cells not having enough nutrients and not being able to work properly. There are hints that this may be one of the reasons why cancer overcomes the immune system's defence and grows. A new non-invasive technique, called hyperpolarised magnetic resonance imaging (MRI), measures the level of nutrients eaten by the cancer. In patients who were tested with this new type of MRI prior to surgery, I will study what T cells look like and how they work.

Potential applications and benefits: This study will help show how the immune system and kidney cancer work together. When patients are diagnosed with early kidney cancer, we are not able to tell the difference between who can just be monitored and who will need a lot of treatment. Looking closely at the relationship between the immune system and early kidney cancer might help guide treatment and improve patient care. The findings of this study could also be applied to kidney cancer at later stages or other cancers.

Note: public and patients have been involved in writing this summary - patient representatives known to the Specialist Centre for Kidney Cancer (Royal Free London NHS Foundation Trust) have contributed, as well as patients and public through an activity promoted with the support of the UCL Joint Research Office.

Context: The immune system has an important role in the recognition and elimination of malignant cells. There is clinical evidence of cancer immune surveillance in the kidney but the phenotype and functional profile of the immune cells controlling early cancer development remains unknown. Half of renal cell carcinomas (RCC) are diagnosed at early stage but the biology of early RCC is understudied. I want to improve the knowledge on immune-related disease progression events associated with early RCC.

Aims: The primary aim is to explore the T cell profiles associated with progression in early RCC. The secondary aim is to investigate the impact of environmental nutrient deprivation in kidney cancer on T cell function.

Methodology: Patient blood and tissue samples will be used. Primary aim: phenotypical and functional characterisation of T cell subsets associated with shift to escape in early RCC will be done using flow cytometry, immunohistochemistry (IHC), and transcriptomics. Progression-related changes in intratumoural clonal distribution of T cells will be sought after with TCR repertoire analysis. Secondary aim: phenotypic and functional characterisation of tumour T cell subsets using flow cytometry, IHC, and transcriptomics will be done on a cohort of patients that underwent non-invasive tumour metabolic assessment using hyperpolarised MRI.

Scientific and medical opportunities: Innovative experimental and analytic pipelines will generate high quality outputs, contributing to one of the world's leading efforts in applied early cancer research. Elucidating T cell immune mechanisms associated with early RCC progression will lead to biomarker development, improved risk stratification, and ultimately the adoption of more personalised management decisions. While the project focuses on early RCC, a high level of translatability of methods and outputs to other disease stages, cancers, and study designs (i.e. longitudinal monitoring) is expected.

The immune system has an important role in the recognition and elimination of cancer cells. When immune defence is altered, the likelihood of cancer arising in the kidney increases. Likewise, cancer can avoid the killing action of the immune system, a process thought to be essential for cancer growth. T cells appear to play a significant role in the interaction with cancer cells. However, we still don't know exactly what is the nature of this interaction.

Early cancer and specially the mechanisms that govern early cancer development are understudied. Improvement in health service provision and increased use of imaging techniques have led to a high rate of diagnosis of asymptomatic early kidney cancer. While some of the early kidney cancers do grow and spread through the body, others remain stable over time, and do not limit life or quality of life. Currently, our discriminating ability between these two subgroups of early disease is poor. Thus, there is an unmet need to understand early kidney cancer development.

The main aim of this project is to investigate the role of T cells in early kidney cancer growth using clinical samples. The impact goals of the project are:

1) To generate world leading research and knowledge into the immunological basis of early kidney cancer.
This research will lead to high quality outputs that will be disseminated, including published results and data made publicly available that can extend scientific discoveries beyond the scope of this project. This will contribute to academic advancement, to increased international competitiveness of UCL and the UK, and will place the collaboration between the Specialist Centre for Kidney Cancer and the Institute of Immunology and Transplantation as one the world's leading efforts for this kind of research. The outputs of this project are cross disciplinary and will be of interest to immunology, cancer biology, urology, other surgical specialties, oncology, pathology, and bioinformatics.

2) To encourage research into the events behind early kidney cancer development.
I will contribute towards the development of other ventures and collaborations by curating the UCL-RFH biobank kidney cancer repository and encouraging other groups at national and international forums to make use of the samples stored (pending ethical approval). In addition, letters/comments will be published in high-impact factor journals to raise awareness for the need to invest intellectual and financial resources into understanding early cancer development.

3) To define public and patient driven standards in basic and translational kidney cancer research.
Public and patients stand to benefit from well conducted, high impact research. Likewise, service users can greatly impact research in a number of ways. This project will foster the creation of a Patient Advisory Panel following NIHR INVOLVE guidelines to define strategies to increase patient participation in research, identify research priorities in kidney cancer, assist in the dissemination output of challenges and results of the current project, and support the development of future research projects.

4) To generate hypotheses for further validating translational research.
The outputs of this project can contribute to biomarker development, improved risk stratification, and ultimately the adoption of more personalised management decisions. This has the potential to positively impact society and the NHS by upgrading the service provided to kidney cancer patients, improving patient quality of life, and potentially reducing cost. The Specialist Centre for Kidney Cancer is perfectly positioned to lead following validating studies, contributing towards UCL's and UK's international competitiveness. In addition, the research outputs can also generate commercial interest from companies investing in immunotherapy for example, and attract more research partnership initiatives to UCL and the UK.