Project Details
Projekt
The Yin and Yang of anti-cancer CD4+ T cell responses in ALL
Subject Area
Hematology, Oncology
Term
since 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 444949889
Adaptive immunity plays a central role in cancer immune surveillance. Tumor-specific CD4+ T helper (Th) cells initiate and orchestrate adaptive anti-tumor immunity. They may exert opposing functions as protective effector T cells (Teff) and immunosuppressive cells, such as Foxp3+ regulatory T cells (Tregs). However, the effector and regulatory Th cell subsets targeting potential ALL target antigens in patients and healthy individuals, as well as the role of different types of target antigens are currently not well understood. Finally, it is emerging that the microbiome has significant impact on modulation of immune responses and immune surveillance of cancer. How individual species of the microbiota may modulate antigen-specific immune responses, e.g. via T cell cross-reactivity is also poorly characterized. These uncertainties about fundamental tumor-specific immune mechanisms complicates targeted development of novel antigen-specific diagnostics and immunotherapeutic approaches. Therefore, the characterization of ALL-specific T cell mediated tolerance and immunity and its modulation by the microbiota will be key to understand immunogenicity of tumors and for the development of antigen-targeted diagnostics and therapies. In our previous work we have developed sensitive technologies to measure antigen-specific T cell responses directly from human blood and with high precision. In preliminary experiments we characterized from healthy donors CD4 naïve and memory T cell reacting against tumor-associated antigens and especially against various neoepitopes derived from ALL-associated gene fusion events. Furthermore, we have screened and identified microbiota which induce T cell reactions in humans. These antigen-specific T cells can readily be isolated for deep functional and molecular characterization, including RNA/TCR sequencing, TCR affinity, cross-reactivity and specificity measurements.In our project, we propose to characterize Treg and CD4+ Teff responses against ALL-associated antigens in healthy donors, as well as in adult and pediatric ALL patients and determine a potential impact of the microbiota. We will first characterize Treg and Teff cell response against different types of leukemic antigens in young and old healthy donors. We will also define microbiota-mediated modulation of anti-tumor T cell immunity in young and old healthy donors and ALL patients. Finally, the functional analysis of tumor-reactive T cells and specific TCRs and the correlation of specific T cell status with response to therapy & disease outcome in pediatric and adult patients will be performed. Overall, this project will define the cellular basis of successful or failing immune surveillance and will accelerate targeted development of immunotherapies.
DFG Programme
Clinical Research Units
Subproject of
KFO 5010:
CATCH ALL Towards a Cure for Adults and Children with Acute Lymphoblastic Leukemia (ALL)
International Connection
Switzerland
Cooperation Partner
Professor Dr. Roland Martin
