Projektbeschreibung
Gibt es eine Verbindung zwischen Darmmikrobiom und Tumorimmunität?
Neue Erkenntnisse lassen darauf schließen, dass Tumor-Neoantigene mit höherer Wahrscheinlichkeit immunogen sind, wenn sie mit Infektionskrankheiten assoziierten Antigenen ähneln, da sie dann eher von den T-Zellen erkannt werden. Ausgehend von dieser Beobachtung zielt das EU-finanzierte Projekt VACCIBIOME darauf ab, die Verbindung zwischen Krebsimmunität und Darmmikrobiom zu untersuchen. Die Hypothese lautet, dass periphere T-Zellen, die Antigene des Mikrobioms verarbeiten und präsentieren, gleichermaßen in Tumoren eindringen und mit Krebsantigenen kreuzreagieren. Die Forschenden werden die molekulare Mimikry des Darmmikrobioms und der Krebsantigene untersuchen und ihre Bedeutung für die Tumorimmunität beschreiben. Als ultimatives Ziel gelten wirksamere Impfstoffe gegen Krebs.
Ziel
This proposal intends to shed light on the interplay between cancer immunity and gut microbiome as a way to optimize personalized cancer vaccines and immunotherapy. The project originates from two milestone discoveries. First, to be effective cancer immunotherapies have to target CD4+/CD8+ T cell neo-epitopes, which originate from tumor mutations. Second, the gut microbiome influences the effectiveness of anti-PD-1/PD-L1 antibody immunotherapy both in animal models and in humans. We also recently showed in a mouse model that oral gavages with Bifidobacterial cocktails improved the therapeutic power of neo-epitope-based cancer vaccines. How microbiome affects anti-cancer immunity has not been fully elucidated yet and a deep understanding of the underlying mechanisms has the potential to substantially improve cancer immunotherapy. Since microbiome antigens are processed and presented by antigen-presenting cells and microbiome-induced T cells represent large fraction of the peripheral T cell repertoire, our hypothesis is that this large repertoire includes T cells which cross-react with cancer neo-epitopes (“molecular mimicry (MM)”). Depending upon the composition of gut microbiome, cross-reacting T cells can positively or negatively modulate anti-tumor immunity. To demonstrate the role of MM in cancer immunity this project intends (i) to select the cross-reactive T cell epitopes as predicted by meta-omics analysis of gut microbiome and exome/transcriptome analysis of cancer cell lines, (ii) to formulate vaccines containing different combination of cross-reactive epitopes, and (iii) to test vaccine anti-tumor activities in normal mice, gnotobiotic mice and mice with engineered microbiome. The ultimate goals are: 1) to provide new criteria for neo-epitope selection in personalized cancer vaccines, 2) to develop prognostic tools based on microbiome analysis, and 3) to define microbial species to be used as immune-potentiators in patients undergoing cancer therapy.
Wissenschaftliches Gebiet
- medical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsvaccines
- natural sciencesbiological sciencesgeneticsmutation
- medical and health sciencesclinical medicineoncology
- medical and health sciencesbasic medicineimmunologyimmunotherapy
- natural sciencesbiological sciencesmicrobiology
Schlüsselbegriffe
Programm/Programme
Thema/Themen
Finanzierungsplan
ERC-ADG - Advanced GrantGastgebende Einrichtung
38122 Trento
Italien