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
CD4 T helper (Th) cells are central organizers of adaptive immune responses and play a critical role in the immune surveillance of cancer. Their contribution may be bidirectional: While cancer antigen-specific effector Th cells (Teff) orchestrate the effective control of cancer growth, Foxp3+ regulatory T cell (Tregs) prevent immune control and support cancer growth. How ALL-related antigen-specific CD4 T cells impact on ALL development and therapy and how age and environment shape the specific Th cell response against ALL is poorly understood. In the first funding period we have analyzed human CD4 T cell responses against ALL-related neoantigens as well as tumor-associated antigens (TAA) in healthy donors. We demonstrated that the anti ALL repertoire is significantly modulated, as indicated by the presence of pre-existing memory Teff and Treg responses in healthy donors. This can result from cross-reactivities against environmental antigens and our preliminary data identified first microbiota candidates. Alternatively, physiological exposure to TAA, which represent physiological self-antigens, may modulate the T cell response, e.g. by formation of specific Tregs. Other peripheral tolerance mechanisms include T cell exhaustion, which we recently described for autoreactive Teff cells, and which seems to be common in adult donors. In the second funding period we want to further characterize these pre-existing ALL-antigen-specific memory Teff and Treg cells, define the mechanisms of their generation and maintenance, their modulation by self or exogenous antigen exposure and determine their potential for therapeutic applications, including identification of high-affinity ALL-antigen specific TCRs. To address these questions, we will use our established antigen-reactive T cell enrichment (ARTE) to characterize ex vivo CD4 T cell responses against ALL-TAA in healthy donors and perform deep characterization, including multidimensional phenotyping or RNA and TCR sequencing as well as functional studies including measurement of TCR affinities and antigen cross-reactivities against microbial candidates. In this way we will identify tumor-specific TCRs with functional features predisposing them for therapeutic applications, such as high affinity, recognition of frequent peptide/HLA combinations, public TCRs (reduced risk of toxicity), and defined cross-reactivity to microbiota. Finally, we will address the question, whether TAA/neoantigen-specific T cells or their TCRs recognize the corresponding antigens in the physiological context of ALL cells and may be beneficial for therapeutic applications. Together, this project shall form the basis for targeted CD4 T cell therapies.
DFG Programme
Clinical Research Units
