Descrizione del progetto
Esiste un legame tra il microbioma intestinale e l’immunità tumorale?
Nuove prove indicano che i neoantigeni tumorali hanno maggiori probabilità di essere immunogenici se assomigliano agli antigeni associati a malattie infettive, poiché è più probabile che siano riconosciuti da una cellula T. Partendo da questa osservazione, il progetto VACCIBIOME, finanziato dall’UE, intende esaminare il legame tra l’immunità al cancro e il microbioma intestinale. L’ipotesi è che le cellule T periferiche che elaborano e manifestano gli antigeni del microbioma si infiltrino anche nei tumori, reagendo in modo incrociato con gli antigeni del cancro. I ricercatori si occuperanno di valutare il mimetismo molecolare del microbioma intestinale e degli antigeni tumorali, stabilendone l’importanza nell’immunità tumorale. In definitiva, ciò dovrebbe tradursi in vaccini antitumorali più efficaci.
Obiettivo
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.
Campo scientifico
- medical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsvaccines
- natural sciencesbiological sciencesgeneticsmutation
- medical and health sciencesclinical medicineoncology
- medical and health sciencesbasic medicineimmunologyimmunotherapy
- natural sciencesbiological sciencesmicrobiology
Parole chiave
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-ADG - Advanced GrantIstituzione ospitante
38122 Trento
Italia