Descripción del proyecto
Reevaluar la inmunovigilancia tumoral bajo un prisma diferente
La inmunovigilancia tumoral sigue siendo un gran enigma en inmunología. Los datos disponibles indican que la activación de los linfocitos T por parte de los antígenos tumorales depende del contexto, y los modelos experimentales utilizados para estudiar el fenómeno no siempre reflejan la situación «in vivo». Para hacer frente a este problema, el proyecto financiado con fondos europeos NeoTs expresará neoantígenos demostrados o predichos en modelos murinos en condiciones de reposo para determinar la naturaleza de los antígenos capaces de inducir linfocitos T funcionales así como el destino a largo plazo de estos últimos. Los resultados ayudarán a aclarar si los mejores antígenos diana se mantienen o se pierden antes de que el cáncer se manifieste clínicamente, lo cual representa una cuestión de gran importancia clínica.
Objetivo
An old question in tumor immunology is whether cancer cells can spontaneously activate T cells that in turn destroy them, termed immunosurveillance. While firmly established for virus-associated tumors, immunosurveillance of spontaneous tumors is still controversial. Intuitively, autochthonous cancer models may be better suited than transplantation model to address this question, yet current models bear pitfalls and do not resemble the sporadic nature of human cancer. Importantly, they are not conclusive. Cancer cell transplantation is artificial and induces acute inflammation, facilitating T cell activation. It may be suited, however, if tumor antigen expression and cell proliferation can be regulated and induced when resting conditions have been re-established.
We will investigate, in two novel cancer models, the fate of T cells specific for naturally occurring mouse and human neoantigens under resting conditions, resembling pathophysiologic conditions. We hypothesize that induction of a large foreign antigen harboring several epitopes, but not a mouse point-mutant neoantigen, activate functional T cells under resting conditions, while both will do under acute inflammatory conditions. We further conditionally express human mutations, either proven or predicted neoantigens, in cancer cells syngeneic to mice with a diverse human T cell receptor repertoire restricted to HLA-A2. Our studies will answer the questions, whether the initial antigen encounter induces functional or dysfunctional T cells, what distinguishes antigens that can or cannot induce functional T cells, what is the long-term fate of the T cells, why are spontaneous T cell responses rare relative to mutation load and how precisely can neoantigens be predicted.
This project will clarify the role of immunosurveillance and addresses the question whether the best target antigens are retained or lost before cancer becomes clinically apparent, which is of high clinical relevance.
Ámbito científico
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Régimen de financiación
ERC-ADG - Advanced GrantInstitución de acogida
13125 Berlin
Alemania