Cancer therapy directed against repressive immune checkpoints that tumors exploit to escape immune attack has seen enormous success. However, checkpoint receptor signaling is incompletely understood, causing fundamental questions on why effective anti-checkpoint therapy is limited to only a few cases to remain elusive. Illuminating underlying molecular signaling mechanisms - the goal of this project - is required to understand and find new ways to combat tumor evasion. The proposed research will address which proteins participate in checkpoint receptor signaling and reverse ligand signaling. Novel proximity proteomics methods and state-of-the-art mass spectrometry will provide the means to d...

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Cancer therapy directed against repressive immune checkpoints that tumors exploit to escape immune attack has seen enormous success. However, checkpoint receptor signaling is incompletely understood, causing fundamental questions on why effective anti-checkpoint therapy is limited to only a few cases to remain elusive. Illuminating underlying molecular signaling mechanisms - the goal of this project - is required to understand and find new ways to combat tumor evasion. The proposed research will address which proteins participate in checkpoint receptor signaling and reverse ligand signaling. Novel proximity proteomics methods and state-of-the-art mass spectrometry will provide the means to discover new modes of checkpoint regulation in T-cells. Especially important in this context is the ability to precisely measure phosphorylation kinetics restricted to the receptor signaling macromolecular complex, which will be uniquely accessible through a new phospho proximity-proteomics approach. Extending the known repertoire of immune checkpoint ligands by cell surface scanning with molecular receptor-proximity probes as pioneered in this study will be a complementary and unbiased approach for immune receptor deorphanization with far-reaching implications for immuno-oncology. Ultimately, resolving checkpoint signaling in the immune-repressive micro-environment of malignant tumors will show how cancers exploit these checkpoints. It is clear that immunology research is at a turning point, because advanced mass spectrometry is poised to decode immune-regulation at an unprecedented pace in the next years. The proposed project will initiate transformative changes that result from immunological research joining forces with modern mass spectrometry. Lastly, deep proteomics of clinical formalin-fixed tumor biopsies will become instrumental for an integrated understanding of disease progression and unlock enormous diagnostic and predictive potential for cancer therapy.

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