Periodic Reporting for period 3 - T-NHL SUPRESSORS (Tumor suppressor pathways counteracting oncogenic immune receptor signaling in T-Cell Lymphoma)
Reporting period: 2022-12-01 to 2024-05-31
T cell non-Hodgkin lymphomas (T-NHLs) are highly aggressive malignancies that are largely resistant to conventional therapies. T-NHLs remain significantly understudied, and their pathogenic mechanisms are still not well defined. We recently identified the inhibitory immune receptor PD-1 as a key tumor suppressor in T-cell lymphoma that is inactivated in up to 30% of human cases (Wartewig et al., Nature 2017). Based on these findings, the overall goal of this project is to comprehensively model and dissect T-cell lymphomagenesis driven by aberrantly activated T-cell receptor pathways and to identify the PD-1-dependent and -independent tumor suppressor mechanisms that inhibit these events. We expect that our results will provide fundamental new insights into the molecular pathomechanisms of highly aggressive T cell cancers and additionally lead to the identification of new factors that inhibit antigen-mediated T cell activation.
Using a genome-wide screen, we have identified a series of potential regulators of PD-1 signaling. After validating these initial hits via a CRISPR/Cas9 approach, we created different model systems which we are now using to dissect the contribution of the candidate regulators to T-cell lymphomagenesis and their role in PD-1 signaling in detail. In addition, we generated mouse models for further T-NHLs driven by T cell specific oncogenes.
So far, we have identified different druggable targets and mechanisms of T-cell lymphomagenesis such as effectors of the PD-1 signaling pathway. We expect to expand our findings by the end of the funding period and thus provide novel targets for immune-oncological therapy approaches.