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

Projektbeschreibung

Charakterisierung von T-Zellen gegen Krebs-Neoantigene

Die Aktivierung des Immunsystems zur Bekämpfung von Krebs ist ein vielversprechendes Konzept, das bisher jedoch nur begrenzte Erfolge erzielte. Es scheint nur bei einer Untergruppe von Patientinnen und Patienten wirksam zu sein, und die Immunsuppression sowie die Identifizierung der immungenetischen Zielstrukturen des Krebses stellen weiterhin große Herausforderungen dar. Im EU-finanzierten Projekt Tumour T cells sollen die Immunantworten gegen von mutierten Tumorproteinen produzierte Neoantigene untersucht werden. Die Wissenschaftlerinnen und Wissenschaftler werden die spontanen antitumoralen T-Zell-Antworten mit und ohne Vorliegen akuter Entzündungserscheinungen sowie den Einfluss dieser T-Zell-Antworten auf die Tumorabstoßung untersuchen. Die Charakterisierung der neoantigenspezifischen T-Zellen wird wichtige Erkenntnisse zur Krebsimmunüberwachung liefern und einen Beitrag zur zukünftigen Entwicklung effektiverer Interventionen leisten.

Ziel

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.