Spontaneous and therapy-induced immune response in mice and men (Prof. Dr. Willimsky)
Cancer cells can be recognized by T cells, the success story of checkpoint inhibitors such as anti-cytotoxic T lymphocytes antigen 4 (CTLA-4) and anti-programmed death 1 (PD-1) has reinforced this notion. Whether destructive or non-destructive spontaneous T cell responses are induced in the autochthonous host is dependent on the inflammatory conditions in which the cancers develop.
Development of clinically relevant mouse cancer models and the analysis of the spontaneous and therapy-induced immune response against non-transplanted cancers are central objectives of the Experimental and Translational Cancer Immunology Group. To this end sporadic and virus-induced cancer development using conditional cancer antigen expression by Cre/LoxP system in genetically engineered mouse models have shown profound cancer-induced systemic tolerance already at the premalignant stage of sporadic cancers on the one hand and induction of systemic immunity but local antigen specific cytotoxic T cell (CTL) tolerance in virus-induced cancers on the other hand. Spontaneous and therapy-induced T cell response in these cancer models are investigated in the presence or absence of chronic inflammation and under the influence of different diets.
In the future the autochthonous cancer models will also be further developed with therapeutically relevant human somatic mutations and viral oncoproteins as cancer-specific antigens using CRISPR/Cas system and spontaneous and therapy-induced T cell response against strong and weak antigens will be analyzed simultaneously. In general, these autochthonous cancer models offer the possibility to test immunotherapies based on defined antigens for targeted clinical applications. Here our major focus is on adoptive T cell therapy to combat cancer. In this respect CRISPR/Cas system not only ensures de novo expression of corresponding targets, but also allows, in the presence of different human MHC haplotypes, to test the efficiency of T cell receptor (TCR) gene-modified T cells in vivo in a clinically relevant context. This also includes the identification of relevant human immunogenic cancer rejection antigens as well as generation of human TCRs with optimal affinity. Suitable TCRs will be pursued into clinical application.
Prof. Dr. Gerald Willimsky
Institute of Immunology (Charité - Universitätsmedizin Berlin)
and German Cancer Research Center (DKFZ)