Descripción del proyecto
¿Existe un vínculo entre el microbioma intestinal y la inmunidad tumoral?
Pruebas de nueva aparición señalan que los neoantígenos tumorales tienen más probabilidades de ser inmunogénicos si se parecen a los antígenos asociados a enfermedades infecciosas, porque es más probable que sean reconocidos por un linfocito T. A partir de esta observación, el proyecto VACCIBIOME, financiado con fondos europeos, tiene por objeto investigar el vínculo entre el microbioma intestinal y la inmunidad tumoral. La hipótesis es que los linfocitos T periféricos que procesan y presentan antígenos del microbioma también se infiltran en los tumores y reaccionan de forma cruzada con los antígenos tumorales. Sus investigadores examinarán el mimetismo molecular del microbioma intestinal y los antígenos tumorales y determinarán su importancia en la inmunidad tumoral. En último término, se espera que esto conduzca a vacunas antineoplásicas más eficaces.
Objetivo
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.
Ámbito científico
- medical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsvaccines
- natural sciencesbiological sciencesgeneticsmutation
- medical and health sciencesclinical medicineoncology
- medical and health sciencesbasic medicineimmunologyimmunotherapy
- natural sciencesbiological sciencesmicrobiology
Palabras clave
Programa(s)
Régimen de financiación
ERC-ADG - Advanced GrantInstitución de acogida
38122 Trento
Italia