Rolle der Mikrobiom-abhängigen „Tumor-induzierten Entzündung“ im kolorektalen Karzinom
Zusammenfassung der Projektergebnisse
Colorectal cancer is the third most common cancer worldwide and remains the second leading cause of death among all cancers in the westernized world, despite significant progress in detection, surgery and chemotherapy. The majority of these deaths stem from metastatic relapse. CRC tumors display robust inflammatory infiltration and cytokine expression, which are essential for tumor progression and are associated with poor prognosis. Therefore, the search for new therapy options and the identification of immunological mechanisms is crucial. The basic science projects at the host institution (Comprehensive Cancer Institute, Cedars- Sinai Medical Center) were dedicated to investigating the role of microbiota and microbiotadriven “Tumor-elicited inflammation” (TEI). The microbial burden was identified as promoting primary tumors in the colon and contributing to the creation of a metastatic niche in the liver, thereby promoting tumor growth. We were able to show that microbiota regulates IL-17-driven pro-inflammatory and pro-tumorigenic pathways. Neutralization of IL-17A led to tumor reduction. Analysis of immune cells revealed that IL-17A promotes the recruitment of tumorassociated macrophages (TAMs) in the metastatic liver environment. IL-17RC signaling in hepatocytes promotes liver metastasis through early metastatic colonization by recruiting neutrophils and limiting cytotoxic CD8+T and NK cell infiltration. Deletion of IL-17RC receptor in myeloid cells markedly diminished metastatic growth in the liver. The IL-17 pathway can also be affected through other proinflamatory cytokines. We further revealed the role of IL-27 in colon cancer and liver metastasis development. IL-27 promotes colon carcinogenesis in colitis-associated cancer. IL-27ra is required for colon tumorigenesis in CRC spontaneous models and liver metastasis being promoted through T cell specific IL27R signaling. Further analysis of already collected data will help identify the exact molecular mechanisms of IL-27ra signaling in colon carcinogenesis and may potentially promote development of further immunotherapeutics for advanced CRC.
Projektbezogene Publikationen (Auswahl)
-
Molecular Mechanisms of Tumor Immunomodulation in the Microenvironment of Colorectal Cancer. International Journal of Molecular Sciences, 23(5), 2782.
Plundrich, Dorothea; Chikhladze, Sophia; Fichtner-Feigl, Stefan; Feuerstein, Reinhild & Briquez, Priscilla S.
