The interaction of T-cell receptors (TCR) with major histocompatibility complex (MHC) class Imolecules and antigenic peptides (TCR-p-MHC) is highly important for the recognition ofvirus- or tumor-derived antigenic peptides by the adaptive immune system. We havepreviously identified a high number of potentially recognizable peptide epitopes derived fromprimary tumor samples as well as several TCR with specificity for some selected peptideligands, which may be useful for clinical application in diverse malignancies. However, despite intensive experimental testing, therapeutic application still harbors risks regardingsafety and efficacy. Improved understanding and modeling of the TCR-p-MHC interactionmay therefore be of high relevance. Using our designated expertise in computationalmethods of p-MHC interaction, we now plan to combine bioinformatics and experimentaltechniques for the development and optimization of cancer-specific TCR. We will focus onthe affinity prediction of peptides identified by immunopeptidomics to MHC in order tofacilitate the selection of most promising epitope candidates. Moreover, we will develop algorithms for TCR-p-MHC docking in order to predict peptide specificity of the TCR as well as mimotopes potentially recognized by selected TCR candidates. Such algorithms will potentially also allow optimization of TCR complementary determining regions (CDR) forenhanced specificity and function. Taken together, the project will be highly relevant forinvention of novel anti-tumor immunotherapies and impacts on efficacy, safety and economicaspects.