Transcriptional regulation and therapeutic modulation of cytotoxic function in tumour-infiltrating CD4+ T cells
Lead Research Organisation:
University College London
Department Name: Cancer Biology
Abstract
The immune system may hold the key to combating cancer. Recent cancer immunotherapy approaches have been focused on boosting or re-invigorating cytotoxic CD8+ T cell function. However, the proportion of patients that do not respond to therapy remains high and some tumours are not targeted by CD8+ T cells.
There is growing recognition that CD4+ T helper cells can also acquire cytotoxic effector function, and that these cells form a key component of the response to cancer and viral infection. However, our understanding of cytotoxic CD4+ T cell derivation and function lags significantly behind that of their CD8+ counterparts and other CD4+ T cell lineages. Identifying factors that regulate the differentiation and function of cytotoxic CD4+ T cells would provide new opportunities to boost the immune response to cancer and viral infection.
We propose to combine genomics and cancer immunology approaches to identify regulatory proteins that control the differentiation and function of cytotoxic CD4+ T cells in tumours and how these mechanisms may be targeted to harness the activity of these cells.
Building on previous work from our labs, we will use genetically modified tumour models to identify the genes through which transcriptional regulators control differentiation of cytotoxic CD4+ T cell precursors. We will also define the nature of a checkpoint that prevents acquisition of cytotoxic function by precursor cells in untreated tumours. Finally, we will determine whether these regulatory mechanisms can be targeted to promote cytotoxic CD4+ T cell function and tumour immunity.
This work will provide knowledge of the factors that control cytotoxic CD4+ T cell function and identify targets through which the activity of these cells can be harnessed in patients.
There is growing recognition that CD4+ T helper cells can also acquire cytotoxic effector function, and that these cells form a key component of the response to cancer and viral infection. However, our understanding of cytotoxic CD4+ T cell derivation and function lags significantly behind that of their CD8+ counterparts and other CD4+ T cell lineages. Identifying factors that regulate the differentiation and function of cytotoxic CD4+ T cells would provide new opportunities to boost the immune response to cancer and viral infection.
We propose to combine genomics and cancer immunology approaches to identify regulatory proteins that control the differentiation and function of cytotoxic CD4+ T cells in tumours and how these mechanisms may be targeted to harness the activity of these cells.
Building on previous work from our labs, we will use genetically modified tumour models to identify the genes through which transcriptional regulators control differentiation of cytotoxic CD4+ T cell precursors. We will also define the nature of a checkpoint that prevents acquisition of cytotoxic function by precursor cells in untreated tumours. Finally, we will determine whether these regulatory mechanisms can be targeted to promote cytotoxic CD4+ T cell function and tumour immunity.
This work will provide knowledge of the factors that control cytotoxic CD4+ T cell function and identify targets through which the activity of these cells can be harnessed in patients.
Technical Summary
Recent cancer immunotherapy approaches have been focused on boosting or re-invigorating cytotoxic CD8+ T cell function. However, the proportion of patients that do not respond to therapy remains high and some tumours lack MHC I expression.
There is growing recognition that CD4+ T helper cells can also acquire cytotoxic effector function, and that these cells form a key component of the response to cancer and viral infection. However, we lack information on the factors required for the differentiation and function of cytotoxic CD4+ T cells (CD4+ TCTX), especially in tumours.
We have found that acquisition of cytotoxic function in tumour-infiltrating CD4+ T cells requires the transcriptional repressor Blimp-1 and is antagonised by Bcl6. We have also discovered that although Blimp-1 is necessary for GzmB transcription, GzmB protein production in TEFF is inhibited unless TREG are depleted from the tumour microenvironment.
We propose to combine genomics and tumour immunology approaches to identify regulatory mechanisms that control the differentiation and function of cytotoxic CD4+ T cells in tumours and how these mechanisms may be targeted to enhance the function of these cells in tumour immunity.
We have three research objectives:
1. Understand how Blimp-1 and Bcl6 regulate the differentiation of CD4+ cytotoxic precursors in tumours by applying CUT&Tag and scATAC-seq techniques to genetically modified tumour models.
2. Characterise and modulate a checkpoint that restrains GzmB protein production in CD4+ cytotoxic precursors using blocking antibodies and gene editing in tumour models.
3. Determine whether the Blimp-1/Bcl6 axis can be targeted to promote acquisition of cytotoxic CD4+ T cell function using tumour models and patient-derived xenografts.
This work will provide knowledge of the factors that control cytotoxic CD4+ T cell function and identify targets through which the activity of these cells can be harnessed in patients.
There is growing recognition that CD4+ T helper cells can also acquire cytotoxic effector function, and that these cells form a key component of the response to cancer and viral infection. However, we lack information on the factors required for the differentiation and function of cytotoxic CD4+ T cells (CD4+ TCTX), especially in tumours.
We have found that acquisition of cytotoxic function in tumour-infiltrating CD4+ T cells requires the transcriptional repressor Blimp-1 and is antagonised by Bcl6. We have also discovered that although Blimp-1 is necessary for GzmB transcription, GzmB protein production in TEFF is inhibited unless TREG are depleted from the tumour microenvironment.
We propose to combine genomics and tumour immunology approaches to identify regulatory mechanisms that control the differentiation and function of cytotoxic CD4+ T cells in tumours and how these mechanisms may be targeted to enhance the function of these cells in tumour immunity.
We have three research objectives:
1. Understand how Blimp-1 and Bcl6 regulate the differentiation of CD4+ cytotoxic precursors in tumours by applying CUT&Tag and scATAC-seq techniques to genetically modified tumour models.
2. Characterise and modulate a checkpoint that restrains GzmB protein production in CD4+ cytotoxic precursors using blocking antibodies and gene editing in tumour models.
3. Determine whether the Blimp-1/Bcl6 axis can be targeted to promote acquisition of cytotoxic CD4+ T cell function using tumour models and patient-derived xenografts.
This work will provide knowledge of the factors that control cytotoxic CD4+ T cell function and identify targets through which the activity of these cells can be harnessed in patients.
Publications
Hertweck A
(2022)
The TH1 cell lineage-determining transcription factor T-bet suppresses TH2 gene expression by redistributing GATA3 away from TH2 genes.
in Nucleic acids research
Lo JW
(2022)
A population of naive-like CD4+ T cells stably polarized to the TH 1 lineage.
in European journal of immunology
Description | BCL6 inhibitors |
Organisation | Institute of Cancer Research UK |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We generated the hypothesis that BCL6 regulated the function of CD4+ T cells in tumours and that treatment with small molecules that target BCL6 could be used to modulate the function of the cells. We tested the effect of small molecule BCL6 inhibitors on CD4+ T cell function in vitro. |
Collaborator Contribution | Our partners provided small molecule BCL6 inhibitors. |
Impact | Patent: Modulation of T cell cytotoxicity and related therapy. Application number PCT/EP2020/068912 |
Start Year | 2019 |
Description | Collaboration with Martin Turner |
Organisation | Babraham Institute |
Department | Lymphocyte Signalling |
Country | United Kingdom |
Sector | Charity/Non Profit |
PI Contribution | We generated the hypothesis that a particular pathway was regulating the function of CD4+ T cells in tumours. We approached Martin Turner to establish a collaboration to allow us to receive a genetically engineered mouse line to test this hypothesis. We then performed the tumour growth and T cell phenotyping experiments with this mouse line. |
Collaborator Contribution | Martin Turner provided a genetically engineered mouse line for our experiments. |
Impact | None as yet. |
Start Year | 2021 |
Description | Tumour-specific CD4+ T cells with Sergio Quezada |
Organisation | University College London |
Department | UCL Cancer Institute |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We assisted with tumour growth and immunophenotyping experiments and with experimental design. |
Collaborator Contribution | Our collaborators performed all the other work |
Impact | Sledzinska A, Vila de Mucha M, Bergerhoff K, Hotblack A, Franz Demane D, Ghorani E, Arakrca A, Marzolini MAV, Solomon I, Arce Vargas F, Pule M, Ono M, Seddon B, Kassiotis G, Marafioti T, Ariyan CE, Korn T, Lord GM, Stauss H, Jenner RG, Peggs KS, Quezada SA. (2020). Regulatory T cells restrain IL-2- and Blimp-1-dependent acquisition of cytotoxic function by CD4+ T cells. Immunity 52:151-166. A patent application has been made by CRUK Technology to protect the IP established by this work. Funding from CRUK Technology to perform experiments to demonstrate the IP. |
Start Year | 2017 |
Title | MODULATION OF T CELL CYTOTOXICITY AND RELATED THERAPY |
Description | The present invention provides an engineered T cell for use in a method of treatment of a proliferative disorder in a mammalian subject, wherein the T cell has been engineered (i) to overexpress BLIMP1 and/or (ii) to knock-out or decrease expression of BCL6. Further provided is a BCL6 inhibitor for use in a method of enhancing immunotherapy in a subject having a proliferative disorder. Also provided are related methods of treatment employing the engineered T cell and/or BCL6 inhibitor. |
IP Reference | WO2021001567 |
Protection | Patent application published |
Year Protection Granted | 2021 |
Licensed | No |
Impact | None as yet. |
Description | Invited seminar at Barts Cancer Institute |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Professional Practitioners |
Results and Impact | Invited seminar to present our work at the Barts Cancer Institute. This disseminated our work and increased our visibility. |
Year(s) Of Engagement Activity | 2022 |
Description | Presentation at Bridging Innovation and Translation in T cell Immunotherapy conference |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Oral presentation at Immunoctoberfest 2022: Bridging Innovation and Translation in T cell Immunotherapy |
Year(s) Of Engagement Activity | 2022 |
URL | https://www.physio.wzw.tum.de/immunological-symposium-2022/ |
Description | Presentation at the Babraham Institute |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Professional Practitioners |
Results and Impact | Invited seminar to researchers working at the Babraham Institute. This helped cement our collaboration with Martin Turner's research group at the institute. |
Year(s) Of Engagement Activity | 2022 |