Descripción del proyecto
Caracterización de linfocitos T frente a neoantígenos tumorales
La activación del sistema inmunitario para luchar contra el cáncer es un concepto prometedor que por el momento ha tenido un éxito limitado. Este método parece ser eficaz solo para un subconjunto de pacientes, y la inmunosupresión y la identificación de dianas inmunogénicas tumorales siguen siendo grandes retos. El proyecto financiado con fondos europeos Tumour T cells estudiará las respuestas inmunitarias frente a neoantígenos producidos por proteínas tumorales mutadas. Los científicos investigarán las respuestas espontáneas de linfocitos T antineoplásicos en presencia y ausencia de enfermedades inflamatorias agudas y evaluarán cómo afectan dichas respuestas al rechazo tumoral. La caracterización de linfocitos T específicos para neoantígenos ofrecerá una mejor comprensión sobre la inmunovigilancia frente al cáncer y ayudará a diseñar tratamientos más eficaces en el futuro.
Objetivo
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.
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MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinador
13125 Berlin
Alemania