Servicenavigation

Project Details

Back

Projekt Print View

Combined prophylactic and therapeutic vaccination in a preclinical model of MMR-D-related cancer

Subject Area General and Visceral Surgery
Hematology, Oncology
Term from 2014 to 2023
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 266360457
 
Final Report Year 2023

Final Report Abstract

Hypermutated tumors carry a variety of T cell-specific neoantigens. This forms the basis of vaccination strategies for which DNA mismatch repair deficient (MMR-D) tumors are predestined. MMR-D occurs both hereditarily and sporadically. As part of the research project, a preclinical in vivo model for MMR-D tumors was established and the efficacy of immunotherapeutic strategies was investigated. Mlh1-/- mice develop tumors spontaneously due to a biallelic loss of the DNA repair gene Mlh1, which manifest themselves both in the gastrointestinal tract (GIT) and in lymphoid organs (thymus, liver). In the first part of the project, an autologous tumor vaccine was used. The repetitive application of the tumor vaccine delayed tumor incidence (=prophylaxis) and the growth of already established GIT (=therapy) by reducing the tumor burden or disease stabilization and immune stimulation. A different response was observed depending on the tumor lysate used. Detailed analyses showed that, in addition to the tumor mutation burden, the "quality" of the resulting antigens is crucial for the therapeutic response in both prophylactic and therapeutic situations. Lymphoid tumorigenesis was marginally affected, suggesting an entity-specific antigen profile. Based on the observation that the tumors showed an increased intratumoral mutational load in MMR-D target genes and increased immune checkpoint molecules after therapeutic intervention, a combination therapy with an immune checkpoint inhibitor (anti-PD- L1) was used to counteract the vaccine-induced escape mechanisms. It was shown that the combination therapy is clearly superior to the respective monotherapy and in some cases leads to complete remissions. The underlying mechanisms include a reduction in circulating and tumor-infiltrating myeloid suppressor cells, a decrease in PD-L1+/CTLA-4+ splenic T cells, as well as a suppression of the PI3K/Akt/Wnt/TGF signaling pathway in residual tumors. Cumulatively, this leads to increased T-cell infiltration and a reduction in tumorinfiltrating macrophages and neutrophils. With regard to prophylaxis, the first part of the project showed that MLH1-/- mice exhibit mild immunosuppression early during tumor formation, which favors tumor progression. Therefore, a cyclin-dependent kinase inhibitor was used to enhance the body's own immune response. The CDK4/6 abemaciclib significantly delayed tumor development, including the secretion of pro-inflammatory cytokines (IL2, IL6), reduced numbers of immune checkpointpositive T cells and activation of the Hedgehog/Notch signaling pathway in the "late-onset" tumors. These effects were not enhanced by combination with the tumor vaccine. In conclusion, promising therapies for the treatment of MMR-D tumors have been identified and preclinically validated.

Publications

 
 

Additional Information

© 2026 DFG Disclaimer / Copyright / Privacy Policy

Textvergrößerung und Kontrastanpassung