After I finished my training as a Mathematician/Computer Scientist (B.Sc. and M.Sc.), I went on to pursue a medical degree at the Technical University of Munich (TUM). In parallel, I also started work on a research project in the lab of Dr. Jürgen Ruland in the Institute for Clinical Chemistry at the university hospital Klinikum Rechts der Isar within the Ph.D. program "Medical Life Science and Technology". I finished the program in 2020 and worked in the Ruland Lab as a clinician-scientist postdoctoral fellow until March 31, 2021. Within my Ph.D. project “Analysis of tumor evolution in a model of T-NHL”, I developed a transgenic mouse model, which allows for acute activation of oncogenically enforced T cell receptor pathways conditionally in CD4+ T cells in vivo. This model was based on a knock-in mouse, which had been generated previously in our laboratory and which harbors the human T cell Non-Hodgkin lymphoma (T-NHL) derived ITK-SYK fusion kinase in the Rosa26 locus (K Pechloff et al. “The fusion kinase ITK-SYK mimics a T cell receptor signal and drives oncogenesis in conditional mouse models of peripheral T cell lymphoma.“ JEM. 2010; 207(5):1031-44). I observed that the single expression of ITK-SYK in mature CD4+ T cells is sufficient to trigger a massive expansion of these cells. However, this proliferation is only transient and insufficient to drive lymphomas. To identify suppressive pathways, which counteract the full transformation of the oncogene sensitized T cells, I performed an in vivo screen using transposon mutagenesis with the help of the laboratory of Dr. Roland Rad. I discovered that a disruption of the PDCD1 gene, which encodes for the PD1 checkpoint receptor, is sufficient for immediate, full transformation of ITK-SYK driven T cells into aggressive lymphomas which resembled molecular, pathological, and clinical features of the human disease. Along with a bioinformatician from our institute, Dr. Christof Winter, we performed a bioinformatic reevaluation of published human data sets from T-NHL patients and found genomic PDCD1 gene alterations in 23% of all investigated cases. For this analysis, it was very helpful that I had been trained in Mathematics and Computer Science before starting biomedical research. In the murine model, the targeted deletion of only one PDCD1 allele was already sufficient to permit lymphomagenesis, establishing together that PD1 functions as a haploinsufficient tumor suppressor in T-NHL. The PD1 pathway receives high attention in immuno-oncology because it can trigger the dysfunctionality of T cells in suppressive tumor microenvironments. Clinically approved antibodies either directed against the PD-1 receptor or against the ligand PD-L1 can block PD- 1 signaling in cancer patients and enhance T cell-mediated anti-tumor immunity. Based on highly successful clinical results in multiple tumor entities, checkpoint Inhibitors are also currently explored for lymphoid cancers including T-NHLs. However, in T-NHL, the tumor cell is a T cell itself and since PDCD1 acts as a tumor suppressor gene in these malignancies, I explored the consequences of anti-PD-1 or anti-PD-L1 checkpoint inhibition in our transgenic mouse model. Consistent with the genetic inactivation, I found that checkpoint inhibitor treatment massively accelerated the expansion of ITK-SYK expressing lymphomatous T cells leading to fatal organ infiltrations within days. Our results demonstrated that pharmacological interference with PD-1 signaling by checkpoint inhibitors can, in principle, accelerate malignant T cell growth (T Wartewig et al. "PD-1 is a haploinsufficient suppressor of T cell lymphomagenesis". Nature 2017; 552:121-125). Indeed, subsequent results from a clinical phase II trial demonstrated the relevance of this hypothesis for T-NHL patients (L Ratner et al. “Rapid Progression of Adult T-Cell Leukemia-Lymphoma after PD-1 Inhibitor Therapy.” N Engl J Med. 2018; 378(20): 1947-1948). The authors documented the potentially devastating effects of checkpoint inhibitor treatment in T-NHL patients, which we had proposed earlier based on my findings. Dr. Ruland and I summarized these and additional consequences from our study, mechanistic implications, and open questions in the review article “PD-1 Tumor Suppressor Signaling in T Cell Lymphomas.” Additionally, I contributed with bioinformatic analysis of the B cell receptor repertoire and RNAseq analysis on two other publications, “Foxp1 controls mature B cell survival and the development of follicular and B-1 B cells” and “The uric acid crystal receptor Clec12A potentiates type I interferon responses”.