Targeting the disting immunosuppressive functions of CD4+ regulatory T (Treg) cells in cancer
Lead Research Organisation:
University of Cambridge
Department Name: Clinical School
Abstract
T cells coordinate immune function by differentiating into highly specialised cellular lineages that either drive or suppress immune reactions. Whereas effector T cells cause immune activation and can promote clearance of infections and cancer, regulatory T cells, dependent upon the transcription factor Foxp3, powerfully suppress their function, preventing excessive autoimmune and allergic reactions but promoting deleterious immunosuppression in cancer. As a consequence, Treg cells play a pervasive role in health and disease. Mechanisms that control the induction and function of Treg cells are incompletely elucidated. Their discovery will enable development of a powerful new class of therapies aimed at manipulating immune function in patients with autoimmunity, chronic infections and cancer.
The laboratory utilises mouse genetics, cellular immunology and molecular biology to dissect mechanisms that control the development and function of Foxp3+ Treg cells1-3. The aim of this project is to apply a genome-scale functional genetic screening approach to identify genes driving Treg cell differentiation. CRISPR/Cas9-mediated genetic perturbation screening4 will be performed using genome-scale perturbation libraries in pooled populations of Treg precursor cells and the identity of mutations conferring selective enrichment or loss of subsequent Treg differentiation in vitro and in vivo will be recovered using high-throughput sequencing. Validated data will be used to construct a global picture of the complement of factors involved in the differentiation of Treg cells and identified genes will be further validated using CRISPR/Cas9 and conventional mouse genetic and cellular immunology approaches.
The student will gain exposure to a variety of cutting-edge approaches in molecular biology, cellular immunology and molecular biology, including high-throughput sequencing-based techniques. The student will benefit from working in a highly collaborative environment within
The laboratory utilises mouse genetics, cellular immunology and molecular biology to dissect mechanisms that control the development and function of Foxp3+ Treg cells1-3. The aim of this project is to apply a genome-scale functional genetic screening approach to identify genes driving Treg cell differentiation. CRISPR/Cas9-mediated genetic perturbation screening4 will be performed using genome-scale perturbation libraries in pooled populations of Treg precursor cells and the identity of mutations conferring selective enrichment or loss of subsequent Treg differentiation in vitro and in vivo will be recovered using high-throughput sequencing. Validated data will be used to construct a global picture of the complement of factors involved in the differentiation of Treg cells and identified genes will be further validated using CRISPR/Cas9 and conventional mouse genetic and cellular immunology approaches.
The student will gain exposure to a variety of cutting-edge approaches in molecular biology, cellular immunology and molecular biology, including high-throughput sequencing-based techniques. The student will benefit from working in a highly collaborative environment within
People |
ORCID iD |
| Charlotte Imianowski (Student) |
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| MR/R502303/1 | 01/10/2017 | 30/04/2022 | |||
| 1947452 | Studentship | MR/R502303/1 | 01/10/2017 | 30/09/2021 | Charlotte Imianowski |
| Description | AstraZeneca Postdoctoral Research Grant (2 years) |
| Amount | £468,000 (GBP) |
| Organisation | AstraZeneca |
| Sector | Private |
| Country | United Kingdom |
| Start | 04/2022 |
| End | 03/2024 |
| Description | Molecular regulation of NK cell functional maturation by the transcription factor BACH2 |
| Amount | £658,607 (GBP) |
| Funding ID | MR/S024468/1 |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 06/2019 |
| End | 05/2022 |
| Title | Methods for Genome-Wide Measurement and Computational Analysis of Transcription Factor Binding and Chromatin Accessibility in Lymphocytes |
| Description | Cells of the adaptive immune system, including CD4+ and CD8+ T cells, as well as B cells, possess the ability to undergo dynamic changes in population size, differentiation state, and function to counteract diverse and temporally stochastic threats from the external environment. To achieve this, lymphocytes must be able to rapidly control their gene-expression programs in a cell-type-specific manner and in response to extrinsic signals. Such capacity is provided by transcription factors (TFs), which bind to the available repertoire of regulatory DNA elements in distinct lymphocyte subsets to program cell-type-specific gene expression. Here we provide a set of protocols that utilize massively parallel sequencing-based approaches to map genome-wide TF-binding sites and accessible chromatin, with consideration of the unique aspects and technical issues facing their application to lymphocytes. We show how to computationally validate and analyze aligned data to map differentially enriched/accessible sites, identify enriched DNA sequence motifs, and detect the position of nucleosomes adjacent to accessible DNA elements. |
| Type Of Material | Technology assay or reagent |
| Year Produced | 2019 |
| Provided To Others? | Yes |
| Impact | These techniques, when applied to immune cells, can enhance our understanding of how gene-expression programs are controlled within lymphocytes to coordinate immune function in homeostasis and disease. |
| URL | https://pubmed.ncbi.nlm.nih.gov/31483104/ |
| Title | Molecular profiles of mature NK subsets and effect of transcriptional regulator BACH2 on NK cell transcriptional profiles |
| Description | RNA-Seq of Bach2-deficient and WT NK cells RNA-Seq of NK cells in diverse maturation states |
| Type Of Material | Database/Collection of data |
| Year Produced | 2022 |
| Provided To Others? | No |
| Impact | This has shed light on how NK cells develop and contribute to cancer immunosurveillance in tissues |
| Description | Collaboration between the University of Cambridge Department of Pathology and CRUK Cambridge Cancer Institute |
| Organisation | Cancer Research UK Cambridge Institute |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Describing the transcriptional changes associated with NK cell maturation |
| Collaborator Contribution | The research on NK cell maturation and function has fostered a collaboration between my group at the University of Cambridge and that of Dr Tim Halim at CRUK Cambridge Institute, enabling exchange of ideas and reagents |
| Impact | Scientific results (manuscript presently under review); High-content data |
| Start Year | 2020 |
| Description | Collaboration with Crescendo Biologics to develop ways of improving the anti-cancer activity of NK cells |
| Organisation | Crescendo Biologics |
| Country | United Kingdom |
| Sector | Private |
| PI Contribution | By studying negative regulators of NK cell function in tumours, we have discovered an inhibitory pathway that is a potential drug target for augmentation of NK cell function. We are exploring the therapeutic potential of this pathway as part of a collaboration with Crescendo Biologics |
| Collaborator Contribution | Antibody development pipeline. The company will host a member of the laboratory in their organisation to conduct research |
| Impact | None yet |
| Start Year | 2019 |
| Description | Collaboration with Crescendo Biologics to undertake research leading to development of new drugs for individuals with cancer |
| Organisation | Crescendo Biologics |
| Country | United Kingdom |
| Sector | Private |
| PI Contribution | Charlotte Imianowski undertakes a 4 month internship within Crescendo Biologics as part of this CASE studentship and will transfer knoweldge and scientific expertise she has gained during her PhD to Crescendo and assist in their scientific research programme |
| Collaborator Contribution | Charlotte Imianowski undertakes a 4 month internship within Crescendo Biologics as part of this CASE studentship and will benefit from experience in an industrial research environment |
| Impact | None yet |
| Start Year | 2018 |
| Description | BI Student Retreat 2019 |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Postgraduate students |
| Results and Impact | I was one of four organisers of the inaugural Babraham Institute Student Retreat. Taking place at the start of the 2019/2020 academic year as a means of introducing the new PhD students to each other and to existing students, the day was organised in a workshop format. Session topics included introducing each other to specialist techniques, communicating our science in a way that would be accessible to other non-specialist researchers and to the public, a careers session with an invited speaker, and finally a discussion on how best to keep track of the latest literature in our respective fields. Feedback was particularly positive for the science communication session, as communicating science in an accurate yet accessible way to the public is something most students in attendence had found they'd struggled with in the past. |
| Year(s) Of Engagement Activity | 2019 |
| Description | Contribution to Cambridge Festival of Ideas public event on cancer immunology |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Public/other audiences |
| Results and Impact | The inaugural Cambridge Festival, which runs from 26 March - 4 April, brings together the hugely popular Cambridge Science Festival and the Cambridge Festival of Ideas. It hosts an extensive programme of over 350 events that tackle many of the critical global challenges affecting us all, and features hundreds of renowned experts in the field of health and medicine. The key themes are health, society, environment and explore. Over 120 events focus on health. We held a public event on how cancer immunotherapy harnesses the power of our immune system in the fight against cancer: Innovation from Laboratory Bench to Bedside |
| Year(s) Of Engagement Activity | 2021 |
| Description | Ethics Workshop (Healthy Ageing/Animals in Research) for French Sixth Form Students |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Schools |
| Results and Impact | A group of French sixth form students and their teachers took part in an institute-run workshop on healthy ageing and animal research. I was a helper and took charge of a group of these students for the animal research section. We discussed why animals are used in research and why it's important, how to minimise the number of animals we use (3R's) and which models are best for which kind of research. By the end the students had a much greater understanding of what models are used in research and why they are important, and an appreciation of all the considerations researchers take to make sure as few animals as possible are used to fulfil our research aims fully but with minimal suffering. |
| Year(s) Of Engagement Activity | 2018 |
| Description | Interview for local news |
| Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Media (as a channel to the public) |
| Results and Impact | BBC Look East attended the Babraham Institute's 25th Annual School's Day to cover the event, which nearly 200 sixth form students and teachers attended. They interviewed me as a previous attendee of a similar event - which I did as a Sixth Form Student - to ask how it influenced my career goals. This was intended to show the wider regional audience the impact days like these can have on the school students that attend - in my case helping me decide what subject I wanted to study at university, and that I wanted to continue onto the PhD I am doing now. The interview was broadcast that evening as part of the regional news. |
| Year(s) Of Engagement Activity | 2019 |
| Description | Launchpad 2019 Career Talk |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Schools |
| Results and Impact | I gave a talk about my career so far to around 20 12-year-old students and their teachers who were taking part in the Babraham Institute Launchpad event. My talk was intended to give the students an idea of what kinds of things they can study at school to lead to a career in science and what that career can involve. I also gave them a brief introduction to my current research and why it interests me. A Q&A session afterwards involved questions from the students about what it was like to study science at university compared to at school, and why I chose to pursue a career in research. |
| Year(s) Of Engagement Activity | 2019 |
| Description | Participation in an activity, workshop or similar - School visit to the Roychoudhuri laboratory for hands-on experience in flow cytometry and cellular immunology |
| Form Of Engagement Activity | Participation in an open day or visit at my research institution |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Schools |
| Results and Impact | The laboratory hosted a group of 6 sixth form school students to undertake a flow cytometry experiment in cellular immunology with bench research, teaching from PhD and Postdocs in the group |
| Year(s) Of Engagement Activity | 2020 |
| Description | Presentation on the use of mouse models in immunology research |
| Form Of Engagement Activity | Participation in an open day or visit at my research institution |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Public/other audiences |
| Results and Impact | Presentation of the reasons and uses of research using mouse models in immunology research to a large group of local parishioners visiting the Institute for the talk. |
| Year(s) Of Engagement Activity | 2018 |
| Description | School visit to the Roychoudhuri laboratory for hands-on experience in flow cytometry and cellular immunology |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Schools |
| Results and Impact | Two groups of six school children were hosted in the laboratory and were provided hands-on experience processing tissues and using flow cytometry to distinguish populations of lymphoid cells in secondary lymphoid organs using multiparameter flow cytometry. Students were also taught basic scientific background relating to the adaptive immune system |
| Year(s) Of Engagement Activity | 2017 |
| Description | School's Day 2019 Career Talk |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Schools |
| Results and Impact | I was invited to give a talk about my career so far to the roughly 200 sixth form students and teachers who attended the Babraham Institute School's Day. My talk, along with one other given by someone further along in their career was intended to give the students an idea of the different paths a career in science can take them on, as well as some information about the research we were currently working on. A Q&A session afterwards involved questions from the students about what made us choose which degree we wanted to study, and it was clear from talking to some of the students afterwards that they had started to think about which science subjects they wanted to apply for at university. BBC Look East were also in attendance as part of their media coverage of the day, and some parts of this session were used in their broadcast covering the event on the evening news that day. |
| Year(s) Of Engagement Activity | 2019 |
| Description | Symposium of Biological Life Sciences (SymBLS) 2019 |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Postgraduate students |
| Results and Impact | I was one of four organisers of SymBLS 2019, our role involved inviting a number of external speakers, applying for sponsorship and other funding, and organising a panel discussion on this year's theme - failures in science. We also selected a number of students to give talks and coordinated a poster session and image competition via an application process during sign up for the event. SymBLS is an annual multidisciplinary life science symposium organised by University of Cambridge PhD students based at the Babraham Institute. First held in 2007, it aims to inspire and facilitate communication across the university. Accordingly, it has rapidly grown in popularity and student participation, with attendees this year reaching 150 postgraduate students, access for whom is free due to the generosity of our sponsors. Current students working in a vast array of biological disciplines representing the diversity of Cambridge research are afforded the opportunity to give both oral and poster presentations alongside those from keynote speakers who we aim to recruit to inspire their future work and career choices. Feedback from this year's event was overwhelmingly positive, with particular appreciation given to the range of subjects our invited speakers represented, and the lively discussion invoked by this years' panel discussion topic. |
| Year(s) Of Engagement Activity | 2019 |