Targeting defective DNA repair signaling and immune evasion in mantle cell lymphoma

Mantle cell lymphoma (MCL) is a mature B-cell lymphoma characterized by aberrations related to cell cycle dysregulation, DNA damage response and cell survival pathways. In >50% of cases somatic mutations in ATM are observed. Functionally, the kinase ATM is critical for DNA repair, but to date no targeted treatment options exist for this or other high-risk MCL genetic subtypes e.g. with TP53 alterations. Mutational signatures caused by DNA repair deficiencies are further known to shape tumor immune composition which in MCL is poorly understood today. Due to the often aggressive, frequently chemorefractory and fatal disease course, innovative MCL treatments utilizing personalized immunotherapeutic approaches in combination with genetically rationalized agents are urgently needed. My research thus aims to identify and functionally dissect genetic and proteomic vulnerabilities as well as mechanisms of immune evasion in MCL. I aim to expand the toolbox of currently utilized MCL model systems by establishing patient-derived cell lines, organoids and xenografts as well as genetically engineered MCL mouse models. The overarching goal of my research is to determine targetable dependencies in high- and low-risk MCL and provide rationale for novel MCL therapies informed by genetic vulnerabilities and the tumor microenvironment composition.