Universität zu Köln

Ibruli, Olta (2025). Modeling Mismatch Repair Deficiency in Small Cell Lung Cancer. PhD thesis, Universität zu Köln.

PDF (PhD thesis from Olta Ibruli) Dissertation_Olta Ibruli_publication.pdf - Accepted Version Download (5MB)

Abstract

Small cell lung cancer (SCLC) is a highly aggressive malignancy characterized by rapid progression, early dissemination of metastases, and very poor prognosis. Although the introduction of immune checkpoint inhibitors (ICIs) into first-line therapy has shown modest improvement in survival outcomes, most patients remain unresponsive, and predictive biomarkers are lacking. One molecular hallmark of SCLC is its high tumor mutational burden (TMB), attributed mainly to tobacco-induced mutagenesis. However, recent proteogenomic studies have identified a subset of patients (~15%) harboring mismatch repair deficiency (MMRd), including alterations in key MMR genes such as MSH2. This subgroup exhibits unique mutational signatures and poor clinical outcomes. However, it remains largely understudied due to sparse tumor biopsies and a lack of representative preclinical models. To address this gap, this thesis presents the development of a novel genetically engineered mouse model (GEMM) of SCLC by introducing conditional Msh2 deletion into the Rb1/Trp53- deficient (RP) background, generating the RPM model (Rb1fl/fl;Trp53fl/fl;Msh2fl/fl). Using whole-exome sequencing (WES), we demonstrate that RPM tumors with bi-allelic loss of Msh2 successfully recapitulate the genomic landscape associated with MMRd, including a significant increase in TMB, frameshift mutations, and dominant MMRd-associated mutational signatures (SBS15/SBS21). These alterations resulted in a higher load of neoantigens compared to RP tumors. Functionally, RPM tumors displayed significantly increased sensitivity to PD-1 blockade. Furthermore, the RPM mouse model showed improved survival when treated with a Treg suppressor (CDK4/6 inhibitor) in combination with standard-of-care platinum-based chemotherapy and ICI. Additionally, immune profiling via flow cytometry and imaging mass cytometry (IMC) indicates distinct patterns of T cell activation and stromal remodeling in the RPM model compared to RP controls. This thesis provides the first GEMM of SCLC that serves as a physiologically relevant platform to study MMRd in SCLC and highlights the effects of Msh2 loss on tumorigenesis, immunogenicity, and treatment response. These findings have direct implications for developing therapeutic stratification strategies and designing novel treatment regimens tailored to DNA repair-deficient SCLC tumors.