Project description
Revisiting tumour immunosurveillance under a different prism
Tumour immunosurveillance remains a big enigma in immunology. Evidence indicates that the activation of T cells by tumour antigens is context-dependent, and experimental models used to study the phenomenon do not always recapitulate the in vivo situation. To address this problem, the EU-funded NeoTs project will express proven or predicted neoantigens in mouse models under resting conditions to determine the nature of antigens capable of inducing functional T cells as well as the long term fate of the latter. Results will help clarify whether the best target antigens are retained or lost before cancer becomes clinically apparent, a question of high clinical relevance.
Objective
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.
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Funding Scheme
ERC-ADG - Advanced GrantHost institution
13125 Berlin
Germany