NIHRDataInsights/HRCSData huggingface dataset:
Title: Negative feedback control of T cells in tolerance and cancer - from pathways to biomarkers
Funder: Medical Research Council

Abstract: The huge diversity within the T cell receptor (TCR) repertoire allows our immune systems to respond to almost any potential threat; however, such a complex system necessitates negative feedback mechanisms in order to prevent unwanted immune responses and to limit immunopathology. Therefore, all immune responses are counterbalanced through complex, highly dynamic mechanisms which remain incompletely understood. Using the state of the art Nr4a3-Tocky system to monitor and trace peripheral T cell activation in vivo, I have begun to unravel how TCR signalling activates key regulatory modules within T cells in response to antigen in vivo. I hypothesise that these pathways differ in their abilities to regulate T cell responses in both quantitative and qualitative fashions. This proposal seeks to explore how these regulatory pathways activated during tolerance may also account for the exhaustion of immune responses in cancer. Given that most patients do not respond to immune checkpoint blockade therapy, there is an unmet need to understand the complex immunological consequences of checkpoint blockade and identify biomarkers for patients who successfully respond. This proposal will specifically investigate the in vivo mechanisms of action of PD1, Lag3, and IL-10, using the Tg4 tolerance model and extrapolate these findings into both syngeneic (MC38, B16) and autochthonous tumour models (AOM/DSS, Apc-min/+). It will aim to identify early T cell phenotypic markers of effective responses to checkpoint blockade in vivo. In addition, it will investigate how the effector cytokine IFN-gamma feeds back to regulate immunological checkpoints in vivo. Thus, this work will not only lead to a better understanding of the mechanism of action of immunotherapies but will identify priority candidate biomarkers to test in future human samples and cohorts.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;6.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS;INFLAMMATORY AND IMMUNE SYSTEM
Title: Development of a novel anti-cancer NK cell-based immunotherapy.
Funder: Chief Scientist Office, Scotland

Abstract: Our Bodies contain many different immune cells that keep us healthy by fighting off diseases and stopping cancer cells from growing within our bodies. In order to do this, these cells have to know where to go within the body. This movement is controlled by chemicals called chemokines which act as a sort of map, allowing different parts of our bodies to have a “cellular address code”. When we get sick with an infection, or when cancerous cells begin to grow, these chemicals can change to let our cells know something has gone wrong. This will help immune cells move to the right place to do their jobs. However, sometimes our immune cells can get lost, and won’t be able to follow the correct chemical path. When this happens the cells cannot get to where they need to, and they won’t be able to prevent cancer growth to help make us feel better. We aim to hard-wire the address code for cancer into immune cells, so they can always follow the chemicals released by cancerous cells. This will allow immune cells to move into tumours and kill them before they can cause issues. This project will lead to the development of a new cell-based cancer treatment


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS;INFLAMMATORY AND IMMUNE SYSTEM
Title: Using super-resolution microscopy to probe TIGIT signalling in natural killer cells, with a view to developing novel immune therapeutics
Funder: Wellcome Trust

Abstract: Cancer immunotherapy – activating the immune system to attack cancer cells – represents a paradigm shift in cancer treatment. One particular type of immunotherapy that has shown great promise is the checkpoint inhibitors, which utilise antibodies to block inhibitory immune cell receptors (checkpoints) to release the full potential of the immune system to kill cancer cells. However, large groups of patients see no benefits with this treatment. Severe side effects are also a problem. For this reason, research into alternative immune checkpoints is needed. I am aiming to gain a greater understanding about one specific inhibitory receptor, TIGIT, which stands for ‘T cell immunoreceptor with Ig and ITIM domains’. Little is known about TIGIT function at the molecular and cellular level on immune cells. To address this knowledge gap, I will use super resolution microscopy techniques to look at where TIGIT is located on the surface of natural killer (NK) cells and how this changes in cancer. I will also mutate key residues in TIGIT to identify those needed for its inhibitory function. These studies will help explain the mechanisms behind TIGIT’s negative effect and will provide crucial information for guiding the design of novel cancer immunotherapies in the future.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;INFLAMMATORY AND IMMUNE SYSTEM
Title: Investigating the role of IFNg in controlling checkpoint receptor expression in response to immunotherapy
Funder: Wellcome Trust

Abstract: Cancers are composed of mutant self-cells that exploit their environment to grow. The immune system can identify these altered cells as harmful and kill them. However, in some patients this immune response can become dampened over time. This is due to expression of “immune checkpoints” on a population of white blood cells called T cells. These checkpoints act as brakes on the immune response. In recent years, scientists have developed drugs to block these checkpoints, with the aim of releasing the brake on the immune system to attack the tumour (called immune checkpoint blockade ICB). However, ICB is effective in less than half of patients. One of the effects of ICB is to encourage T cells to make the inflammatory cytokine IFN&gamma;, which aids in eliminating the cancerous cells. Our initial studies suggest that some important immune checkpoints, such as Lag3, are increased by the cytokine IFN&gamma;, which may limit the success of ICB therapy. We aim to understand how IFN&gamma; controls these immune checkpoints on T cells in animal models of cancer. By using mice where their T cells cannot sense IFN&gamma; we will test whether making T cells insensitive to IFN&gamma; can improve ICB therapy.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;INFLAMMATORY AND IMMUNE SYSTEM
Title: ‘Harnessing the little white cells’: Tracing practices of immunity in cancer
Funder: Wellcome Trust

Abstract: Immunotherapy has been heralded as a therapeutic revolution as it utilises the patient's own body to treat cancer: (re)invigorating the personalisation agenda in cancer. Clinical concerns have however, been raised regarding long-term treatment side-effects, predicting response and prognosis, and management of patients’ hopes and expectations. Drawing upon interviews and ethnography conducted in two clinical sites implementing immunotherapy treatments as standard of care or in experimental trials, this project asks: (1) How are developments in immunology shifting conceptualisations of what cancer is and how it is treated? (2) How are patients’ experiences and subjectivities configured by immunological developments in cancer treatment? (3) How is immunity in cancer constituted through the material practices of scientists, clinicians and patients within the context of personalised cancer medicine? This project will extend existing debates concerning the societal implications of biomedical developments in oncology with a particular focus on the unfolding practices and everyday experiences of immunotherapy treatments. Empirically it will be one of the first in Medical Sociology and Science and Technology Studies to consider immunotherapy as an emerging technology for treating cancer and will yield novel theoretical findings relating to the implications of this approach for shaping how cancer is understood, practised and experienced.

Lay abstract: Over the last five years, immunotherapy treatments have emerged in clinical practice and are also currently being tested as part of experimental clinical trials to treat patients with some forms of cancer. These treatments utilise the patient's own body to treat cancer and the scientific and clinical hope attached to these novel therapies is that they have the potential to extend survival time for patients. There are however, clinical concerns regarding long-term treatment side-effects and toxicities, predicting response and prognosis, and management of patients’ hopes and expectations. This project involves fieldwork across two sites where treatments are implemented in order to understand how immunotherapy is shifting how cancer is approached, managed and experienced. It considers the way in which immunotherapy treatments impact how cancer is managed in clinical practice as part of patient care as well as exploring what these developments mean for patients who are living with cancer.

Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS;INFLAMMATORY AND IMMUNE SYSTEM
Title: A Single-cell approach to probing proximal TCR signalling and early transcription of cytotoxic T cells
Funder: Wellcome Trust

Abstract: Cytotoxic T cells (‘killer cells’) are a vital component of our immune system. The human body is capable of mounting different responses to ensure defence against foreign invaders such as faulty cancerous cells, whilst protecting useful bodily cells from destruction. Their ‘killing’ ability is the reason cytotoxic T cells are of great interest in the development of cancer treatments. However, more work is required if they can be harnessed as effective and yet safe therapies. Studying cytotoxic T cells is difficult with conventional scientific methods, since our bodies are inherently designed to produce vast populations of T cells, each able to kill different infected or faulty cells. The diversity and rapidity of these responses confer immunological advantages but make deciphering events on a per-cell basis perplexing. This project proposes to use ‘single-cell resolution’ methods to study cytotoxic T cells. Mass cytometry and single-cell RNA sequencing are innovative techniques that are capable of simultaneously measuring multiple changes within each single-cell. Together, these techniques will allow us to gain an in-depth understanding of the regulation of cytotoxic T cells, to improve and expand cancer immunotherapy.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS;INFLAMMATORY AND IMMUNE SYSTEM
Title: Exploring the clonal determinants of T-cell anti-cancer and autoimmune responses after immune checkpoint blockade
Funder: Wellcome Trust

Abstract: This research aims to improve our understanding of how an important immune cell, called a T cell, functions and changes when treated with a class drug called immune checkpoint blockers (ICBs). These drugs have been very successful in treating some forms of cancer - particularly skin cancers - but they don't work for everybody and some people suffer from severe side effects. We will compare the T cells from patients with skin cancer with those from healthy volunteers. We will then analyse what happens to T cells when they are exposed to ICBs. First, we will look at which bits of DNA instructions they turn on and off . Second, we will look at which T cells are implicated in the autoimmune side effects with the objective of identifying which T cells drive these toxic responses. Ultimately, this research will enable us to predict which patients are more likely to benefit from ICBs, and which are at higher risk of side effects, allowing patients and doctors to make better decisions about treatment . Also, by better understanding the autoimmune side-effects, we might gain insight into what goes wrong in many diseases caused by an over-active immune system.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;INFLAMMATORY AND IMMUNE SYSTEM
Title: Cancer Inflammation and Immunity Group
Funder: Cancer Research UK

Abstract: Identification and characterisation of mediators of tumour promoting or inhibitory inflammation: The notion of immune-based control of cancer has historically been controversial but has gained great support from the remarkable clinical success of certain types of immunotherapy over the past few years. This is certainly the case of melanoma, where some patients have shown complete and durable responses upon treatment with immune checkpoint blocking antibodies. Also promising results were obtained in treatment-refractory cancers such as metastatic non-small-cell lung carcinoma, a type of cancer that until recently was considered as unresponsive to immunotherapy. Nevertheless, in all cases, only a fraction of patients responds underscoring the need for mechanistic studies to determine why this is the case. Indeed, how tumours evade natural and therapy-induced immune responses is a long-standing question in cancer biology. The concept that cancer induces inflammation and that inflammatory cells at the tumour site promote several key aspects of malignant tumours such as proliferation, invasion, angiogenesis or migration, is well established. On the other hand, some types of inflammation such as the one characterised by T cell infiltration, particularly by cytotoxic T cells, are associated with a favourable prognosis and clinical benefit. Moreover, effective anti-tumour immunity depends on inflammatory mediators that contribute to the activation of immune cells such as dendritic cells. Together, these observations indicate that cancer-associated inflammation can have both tumour-promoting and inhibitory effects. How different types of inflammation are manipulated by a growing tumour and to what extent this constitutes an opportunity for therapeutic intervention remains incompletely explored. In this context, our group investigates the mechanisms by which cancer cells trigger the immune system and simultaneously evade anti-tumour immunity. The aim of this project will be to identify and characterise factors that modulate the function of immune cells such as dendritic cells in the tumour microenvironment, distinguishing mediators promoting anti-tumour immunity from those that support tumour growth. Building on from our recent work (Zelenay et al. Cell 2015), the successful candidate will evaluate how specific genetic mutations in cancer cells impact in their ability to modulate the recruitment and function of immune cells through a combination of in vitro and in vivo approaches. These will include implementing CRISPR-Cas9 technology for genome editing of cancer cells bearing defined combinations of oncogenic mutations, the use of genetically-engineered transplantable and autochthonous mouse models of cancer and the analysis of samples from cancer patients.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS;INFLAMMATORY AND IMMUNE SYSTEM
Title: Cancer and the immune system
Funder: Cancer Research UK

Abstract: The immune system is intricately involved in all aspects of cancer. While many neoplastic cells are detected and eliminated by immune cells, inflammation is also a fundamental driver of tumourigenesis. Our group is interested in understanding the basic immune-regulatory mechanisms in cancer, focusing on a new type of immune-regulatory cell, called the group 2 innate lymphoid cell (ILC2). More specifically, ILC2 are known to directly influence many pro- and anti-cancer immune pathways, making this cell a challenging but potentially important target to investigate. We are using, and developing, cutting-edge reagents to study how ILC2-driven inflammation is involved in cancer. This research will reveal potential new avenues for immunotherapy. Our research at the CRUK Cambridge Institute leverages our expertise in ILC biology and innate/adaptive immune crosstalk, and many of the strengths of the institute: -Imaging inflammation and cancer -Developing new immune-targeted reagents -Single cell technologies to study the tumour niche -Close interactions with Addenbrooke’s and Papworth hospital


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;INFLAMMATORY AND IMMUNE SYSTEM
Title: Stromal/leukocyte interactions in immunity and tumour progression
Funder: Cancer Research UK

Abstract: • Background Our immune system is our defence against the outside world, but also has the potential to recognise and eliminate tumours. It is a complex system of many different cell types with specific tasks. Whilst we know what each cell type is capable of, the complex ways in which different cells communicate with one another and therefore work together has remained more mysterious. It has only recently been acknowledged that the non-immune cells, broadly termed stromal cells, in fact play an important role in regulating the outcome of immune responses, and is fast becoming one of the most exciting areas of immunology research. • Aims The aim of this project is to understand the interplay between leukocytes and lymphoid stroma, in particular fibroblastic reticular cells (FRCs), and to apply these findings to similar signaling occurring between leukocytes, tumour cells and carcinoma-associated fibroblasts (CAFs). My research questions address several related issues. Firstly, the function of dendritic cells in tumours and their ability to present tumour antigens for tumour rejection. Secondly, how cell-cell contact between dendritic cells and FRCs regulates FRC function, applying these findings to the behaviour of CAFs. Lastly, a study of the changes to FRC and CAF behaviour when exposed to inflammatory mediators and mechanical strain. • Methods Studies will examine FRC biology during lymph node expansion; a reproducible model which will provide solid data on fibroblastic function in immunity. These studies will involve phenotypic analysis by flow cytometry, intravital imaging using fluorescent reporter models and detailed imaging studies in lymphoid tissues ex-vivo complimented by in vitro 3-dimensional culture systems. Screening of the consequences of cell-cell contacts will be addressed using unbiased proteomics approaches using in vitro cocultures. • How the results of this research will be used. These projects will address both our fundamental understanding of immune responses but also the signalling events within the tumour microenvironment which impact tumour progression. Results have long-term potential for translational studies for therapeutic interventions enhancing immune recognition of tumours and improve outcomes for patients.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS;INFLAMMATORY AND IMMUNE SYSTEM
Title: Unravelling the CTLA-4 immune checkpoint: from cell biology to clinical application.
Funder: Wellcome Trust

Abstract: The CTLA-4 pathway is a key immune regulator whose absence or mutation leads to profound autoimmunity. CTLA-4 and its relative CD28 have opposing inhibitory and stimulatory functions respectively and interact with two ligands CD80 and CD86. Despite the key role of this pathway in immune regulation and high profile therapies in tumour immunology, our understanding of how CTLA-4 functionally interacts with its two natural ligands is remarkably incomplete. The aim of this proposal is to generate a robust molecular, cellular and functional framework for CTLA-4 biology which can be used to understand the impact of disease mutations, which are being identified as a result of next generation sequencing programmes, and generate knowledge which can underpin new approaches to manipulation of this key immune axis. We will address three key aims: 1). What is the cellular machinery used by CTLA-4 to capture and transfer ligands between cells? 2). How do CTLA-4 interactions with its natural ligands influence its function? 3). How do clinically identified mutations inform our understanding of the CTLA-4 pathway?

Lay abstract: Our immune system acts like an army with powerful weapons which are used to fight off invading microbes like bacteria and viruses. However, in a number of diseases such as arthritis and diabetes, “T cells” in our immune system attack our own bodies - you can think of this as weapons being fired at the wrong target. Normally, special immune cells called Treg prevent this from happening and Treg carry a protein called CTLA-4 which literally “hoovers up” and destroys the signals that tell T cells to fire. Changes in hoovering efficiency can be critical and people whose hoovers don't work properly develop autoimmune diseases. Despite being essential to our health, we know surprisingly little about how the CTLA-4 system works. In this proposal we will generate detailed new knowledge on how CTLA-4 behaves in different settings. This will allow us to understand precisely what happens when CTLA-4 goes wrong and will enable us to design and apply better treatments for diseases that affect a large number of people.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS;INFLAMMATORY AND IMMUNE SYSTEM
Title: The role of the IgE-FceRI axis in tissue immune-surveillance
Funder: Wellcome Trust

Abstract: IgE is an ancient and conserved immunoglobulin isotype with very potent immune functions, currently best known for its roles in allergy and atopy. All epithelial tissues contain resident cells constitutively binding IgE via the FceRI. Nevertheless, the regulation of IgE responses remains poorly understood and evidence for a role of IgE in host defence is limited. My recent work has demonstrated that damage to skin epithelial cells as a result of topical exposure to environmental pollutants, rapidly induces a unique IgE response, which potently affects the susceptibility to epithelial carcinogenesis. Based on these findings, I now hypothesise that IgE and FceRI+ effector cells confer host-protective tumour-surveillance in human skin. I thus aim to identify IgE-elicited pathways and the mechanism(s) utilised to promote tumour immune-surveillance. Further, I will investigate the regulation of IgE production and the role of IgE-dependent effector cells in human squamous cell cancer of the skin. Results will define how IgE mediates its host defence role and will guide future manipulations of the powerful IgE-FceRI axis for immunotherapy. Results may additionally uncover how ‘unwanted’ allergic pathophysiological IgE responses can be regulated.

Lay abstract: Maintaining the integrity of the skin is essential for health. Consequently, the body has developed sophisticated ways to detect early signs of skin damage and my research will determine how these surveillance systems work. This is vital for understanding how we can safely prevent and treat skin allergy and some types of skin cancer. A protein called IgE is very important in monitoring skin health. It is an ancient antibody and all body-surface tissues contain cells that bind to IgE. My research has shown that IgE and immune cells that bind to IgE protect against the development of skin cancer in mice. I hypothesise that the same is true in human skin. My research proposal will define how IgE mediates tumour protection in humans and my findings will enable us to manipulate this system to treat allergy and cancer.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;INFLAMMATORY AND IMMUNE SYSTEM