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The fate and therapeutic potential of human neoantigen-specific T cells

Project description

Characterisation of T cells against cancer neoantigens

Activating the immune system to fight cancer is a promising concept which has been met with limited success. It seems to be effective only in a subset of patients, while immunosuppression and the identification of immunogenic cancer targets remain big challenges. The EU-funded Tumour T cells project will investigate immune responses against neoantigens produced from mutated tumour proteins. Scientists will examine spontaneous anti-tumour T cell responses in the presence and absence of acute inflammatory conditions and assess how they affect tumour rejection. The characterisation of neoantigen-specific T cells will provide important insight into cancer immunosurveillance and help design more effective interventions in the future.

Objective

Cancer is a global health burden and the second leading cause of death worldwide. In recent years, the development of immunotherapy has revolutionised the approach to cancer therapy. A significant limitation, however, is that it is only effective in a subset of patients and the biggest challenges remain the identification of immunogenic targets on human cancers and overcoming immunosuppression. Neoantigens, which are newly formed antigens that arise from mutated tumour proteins, are promising targets in immunotherapy. With the proposed project, we aim to investigate the immune response against human neoantigens which will be induced in a novel humanised tumour mouse model. This unique mouse model harbours the entire human CD8 TCR repertoire and expresses human HLA-2. We will test whether human neoantigens can elicit spontaneous anti-tumour T cell responses in acute inflammatory versus resting conditions, ultimately leading to tumour rejection. We hypothesise that T cells are not able to reject tumours in absence of acute inflammation, similar to the development of most human cancers. To investigate why neoantigen-specific T cells become dysfunctional and fail to reject tumours, we will characterise the functional state and metabolic phenotype of neoantigen-specific T cells by flow cytometry, metabolomics and TCR sequencing. In addition, we will characterise the TCR repertoire of T cells that cause tumour rejection under acute inflammatory conditions. Lastly, we will compare the therapeutic efficacy of adoptively transferred T cells transduced with newly identified TCRs with neoantigen-based vaccines against large established tumours. Overall, this project will contribute to the understanding of immunosurveillance and establish novel techniques to test predicted neoantigens. The identification of human immunogenic targets has the potential to make a global impact on cancer intervention.

Coordinator

MAX DELBRUECK CENTRUM FUER MOLEKULARE MEDIZIN IN DER HELMHOLTZ-GEMEINSCHAFT (MDC)
Net EU contribution
€ 174 806,40
Address
ROBERT ROSSLE STRASSE 10
13125 Berlin
Germany

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Region
Berlin Berlin Berlin
Activity type
Research Organisations
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Total cost
€ 174 806,40