Periodic Reporting for period 3 - NeoTs (Spontaneous T cell responses against cancer neoantigens)
Période du rapport: 2023-10-01 au 2025-03-31
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.
A better understanding of the interaction of T cells and cancer cell will help to develop novel cancer immunotherapies.
We 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 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 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.
A better understanding of the interaction of T cells and cancer cell will help to develop novel cancer immunotherapies.
We 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 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 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.
We established a tumor model, which allows to regulate proliferation and tumor antigen expression in vivo. In usual tumor models, the injection into mice causes an acute inflammatory response which creates an artifact. In our model, we can wait until the artificial inflammation vanished and then induce tumor cell proliferation and tumor antigen expression. This model better resembles conditions of natural tumor development. In this model, we investigate whether different types of tumor antigens can induce functional T cells or whether T cells recognize the tumor antigen but become dysfunctional. Current data suggest that the type of tumor antigen decides over the fate of the T cells.
In another model, we investigate the quality of naturally occurring human neoantigens. We express different neoantigens in tumor cells that derived from a mouse with a humanized T cell recognition system. Current data suggest that some human neoantigens are immunodominant, while others are not. Bioinformatics or in vitro experiments would not have predicted the immunodominant or the recessive neoantigens. We now analyze the mechanism responsible for the immunodominance.
In another model, we investigate the quality of naturally occurring human neoantigens. We express different neoantigens in tumor cells that derived from a mouse with a humanized T cell recognition system. Current data suggest that some human neoantigens are immunodominant, while others are not. Bioinformatics or in vitro experiments would not have predicted the immunodominant or the recessive neoantigens. We now analyze the mechanism responsible for the immunodominance.
1. A novel cancer model with inducible tumor antigen allows analysis of the interaction between cancer cell and T cell under natural pathophysiological conditions. Expected result: Demonstrate whether or whether not a point-mutant cancer neoantigen can induce functional T cells in a model resembling human tumor development.
2. A novel humanized tumor model established that allows to investigate the immunogenicity of naturally occurring human cancer neoantigens. Expected results: Analyze the immunological mechanism explaining why some neoantigens are immunodominant.
2. A novel humanized tumor model established that allows to investigate the immunogenicity of naturally occurring human cancer neoantigens. Expected results: Analyze the immunological mechanism explaining why some neoantigens are immunodominant.