Description du projet
Existe-t-il un lien entre le microbiome intestinal et l’immunité des tumeurs?
Des preuves émergentes suggèrent que les néoantigènes tumoraux sont plus susceptibles d’être immunogènes s’ils ressemblent à des antigènes associés à des maladies infectieuses, car ils sont plus susceptibles d’être reconnus par un lymphocyte T. Partant de cette observation, le projet VACCIBIOME, financé par l’UE, se propose d’étudier le lien entre l’immunité contre le cancer et le microbiome intestinal. Le postulat est que les lymphocytes T périphériques qui traitent et présentent les antigènes du microbiome s’infiltrent également dans les tumeurs et réagissent de manière croisée avec les antigènes du cancer. Les chercheurs évalueront le mimétisme moléculaire du microbiome intestinal et des antigènes du cancer et définiront son importance dans l’immunité des tumeurs. À terme, ceci devrait déboucher sur des vaccins anticancéreux plus efficaces.
Objectif
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.
Champ scientifique
- medical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsvaccines
- natural sciencesbiological sciencesgeneticsmutation
- medical and health sciencesclinical medicineoncology
- medical and health sciencesbasic medicineimmunologyimmunotherapy
- natural sciencesbiological sciencesmicrobiology
Programme(s)
Thème(s)
Régime de financement
ERC-ADG - Advanced GrantInstitution d’accueil
38122 Trento
Italie