Forscherdatenbank
Prof. Dr. Gerald Willimsky
and German Cancer Research Center (DKFZ)
Lindenberger Weg 80
13125 Berlin
Programm
Cancer Immunotherapy (CI)
Übersicht
Spontaneous and therapy-induced immune response in mice and men
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.
DKTK Junior Group Leader for Cancer Systems Biology
Single-cell approaches have not only revealed a wide variety of cell states, characterized by cells exhibiting striking differences in their transcriptional profile, but have also illuminated the mechanisms underlying state transitions in health and disease. Cellular plasticity and adaptive state changes have recently emerged as a basis for therapeutic resistance in cancer, and a better understanding of how cell state transitions are regulated is critical to develop therapeutic approaches that can overcome therapy resistance.
Our research focuses on understanding the mechanisms driving non-genetic cellular heterogeneity and therapy resistance in malignancy. Using novel single-cell sequencing approaches, we seek to develop new experimental and computational strategies to define altered cell states in both, cancer and immune cells. Our aim is to leverage a data driven strategy combined with single cell genomics and systems biology to address the challenges posed by heterogeneity in cancer, and to develop new strategies to overcome it, with the aim of translating laboratory-based findings into the clinic.