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Cancer Vaccines and Gut Microbiome: a rational approach to optimize cancer immunotherapy

Project description

Is there a link between the gut microbiome and tumour immunity?

Emerging evidence indicates that tumour neoantigens are more likely to be immunogenic if they resemble infectious disease-associated antigens, because they are more likely to be recognised by a T cell. Extending from this observation, the EU-funded VACCIBIOME project aims to investigate the connection between cancer immunity and gut microbiome. The hypothesis is that peripheral T cells which process and present microbiome antigens also infiltrate tumours and cross-react with cancer antigens. Researchers will evaluate the molecular mimicry of gut microbiome and cancer antigens and delineate its importance in tumour immunity. Ultimately this is expected to lead to more effective anti-cancer vaccines.

Objective

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.

Host institution

UNIVERSITA DEGLI STUDI DI TRENTO
Net EU contribution
€ 962 500,00
Address
VIA CALEPINA 14
38122 Trento
Italy

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Region
Nord-Est Provincia Autonoma di Trento Trento
Activity type
Higher or Secondary Education Establishments
Links
Total cost
€ 962 500,00

Beneficiaries (2)