Crosstalk between gut microbiome and immune response during tumor progression of pancreatic neuroendocrine tumors

• Applicant: Professor Dr. Sebastian Krug
• Subject Area: Gastroenterology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 440556722

In recent years, the importance of the inflammatory tumor microenvironment (TME) as a crucial modulator of tumor progression has increasingly been recognized. Inflammatory stromal cells are not only relevant for tumor initiation, progression and metastasis, but also affect response to systemic therapies and development of drug resistance. Most prominently, accumulating evidence indicates that the efficacy of immunotherapeutic approaches such as checkpoint inhibition is significantly modulated by the inflammatory stroma. Recently published studies also suggest that tumor progression and response to immunotherapy are also affected by alterations in the intestinal microbiome. Our own preliminary data demonstrate that tumor-associated macrophages (TAM) exhibit a significant tumor-promoting effect in a genetic mouse model for neuroendocrine pancreatic tumors. In analogy to these murine findings, we observed a close correlation between infiltrating macrophages, tumor proliferation and metastasis in a large cohort of human functionally active and inactive pancreatic neuroendocrine neoplasms. In the murine system, we could demonstrate that the protumorigenic effect of infiltrating macrophages can be significantly inhibited by pharmacological depletion via liposomal clodronate. Interestingly, preliminary analyses in this context confirmed significant changes in the intestinal microbiome during tumor development and progression in the genetic mouse model. Based on these preliminary data, this project aims to characterize the influence of the intestinal microbiome on tumor progression and tumor immunogenicity in a genetic mouse model of pancreatic neuroendocrine neoplasms. In addition, it will elucidate potential synergies between therapeutic manipulation of the microbiome and modulation of the immune response including T cell-targeting and macrophage-targeting approaches. Deciphering the molecular crosstalk between intestinal microbiota and antitumor immune response could pave the way to enhance therapy efficacy in tumors not yet responsive to conventional immune therapy.

• DFG Programme: Research Grants