Demographic change includes population ageing, and incidence rates begin to increase for many types of cancer in middle-aged and elderly people. Traditional cancer treatment includes surgery, chemotherapy, and radiation therapy, while tumour immunotherapy by T cell receptor (TCR) gene transfer represents an alternative form of treatment. The transfer of tumour-specific TCR genes into patient’s peripheral blood lymphocytes targets cancer specifically and effectively. But while patient-derived low-affinity TCRs do not show therapeutic activity, optimal-affinity TCRs, as isolated from newly-generated antigen-negative humanized mice with a diverse human TCR repertoire, can effectively delay tumour regression. X-ray crystallography is a powerful tool of structural biology, which helps researchers to identify the three-dimensional (3D) structures of biological macromolecules such as TCRs complexed to their cognate peptide-loaded major histocompatibility complex (pMHC) molecules. Recent research uncovered the docking topologies of naturally selected TCRs, but therapeutically efficient optimal-affinity TCRs recognizing tumour-associated self-antigens, have not been analysed to date. The exceptional specificity of TCRs is determined by three complementarity-determining regions (CDRs) of the TCR alpha- and beta-chains. Biomedical research on TCR gene therapy and design of future clinical trials will hugely benefit from the identification of CDR-mediated contact points made between therapeutic TCRs and the pMHC on their target cells. TCRabX is an interdisciplinary research project investigating the 3D structures of 13 TCRs complexed to MHC-I or MHC-II, respectively. It connects innovative clinical immunology research in Berlin/Germany and world-class structural biology research in Melbourne/Australia. The proposed research will enhance the health and well-being of citizens in Europe and worldwide by supporting the advancement of cancer immunotherapy approaches.
The long-term consequences of exposure to excess stress on the initiation and progression of many age-related diseases are well established. The period of intrauterine life represents among the most sensitive developmental windows, at which time the effects of stress may be transmitted inter-generationally from a mother to her as-yet-unborn child. The elucidation of mechanisms underlying such effects is an area of intense interest and investigation. Aging, by definition, occurs with advancing age, and age-related disorders result from exposures over the life span of factors that produce and accumulate damage. The novel concept advanced in this proposal is that the establishment of the integrity of key cellular aging-related processes that determine variation across individuals in the onset and progression of age-related disorders may originate very early in life (in utero) and may be plastic and influenced by developmental conditions. We propose that telomere biology and the epigenetic DNA methylation-based aging profile (DNAmAGE) represent candidate outcomes of particular interest in this context. A prospective, longitudinal cohort study of 350 mother-child dyads will be conducted from early pregnancy through birth till one year of age. Specific hypotheses about the effects of maternal stress and maternal-placental-fetal stress biology on newborn and infant telomere length, telomerase expression capacity, and DNAmAGE will be addressed. Serial measures of maternal psychological, behavioral and physiological characteristics will be collected across gestation using an innovative ecological momentary assessment (EMA) based real-time, ambulatory sampling protocol. The proposed study will help identify new strategies for risk identification and primary and secondary interventions to augment current efforts to prevent, delay and ameliorate age-related disorders.
Adoptive T cell therapy is a promising approach in various clinical settings, from target-specific immune reconstitution fighting cancer and chronic infections to combating undesired immune reactivity during auto-immunity and after organ transplantation. However, its clinical application is currently hampered by: 1) the acquisition of senescence during the required in vitro expansion phase of T cells which limits their survival and fitness after infusion into the patient, and 2) the functional plasticity of T cells, which is sensitive to the inflammatory environment they encounter after transfusion and which might result in a functional switch from the desired effect (e.g. immunosuppressive) to the opposite one (pro-inflammatory). I want to tackle these obstacles from a new molecular angle, utilizing the profound impact of epigenetic mechanisms on the senescence process as well as on the functional imprinting of T lymphocytes. Epigenetic players such as DNA methylation essentially contribute to T cell differentiation and harbor the unique prospect to imprint a stable developmental and functional state in the genomic structure of a cell, as we could recently show in our basic immune-epigenetic studies. Therefore, I here propose to equip T lymphocytes with the required properties for their successful and safe therapeutic application, including their functional fine-tuning according to the clinical need by directed modifications of the epigenome ('Epi-tuning'). To reach these goals I want: 1) to reveal strategies for the directed manipulation of the epigenetically-driven mechanism of cellular senescence and 2) to apply state-of-the-art CRISPR/Cas9-mediated epigenetic editing approaches for the imprinting of a desired functional state of therapeutic T cell products. These innovative epigenetic "one-shot" manipulations during the in vitro expansion phase should advance T cell therapy towards improved efficiency, stability as well as safety.