Periodic Reporting for period 4 - VACCIBIOME (Cancer Vaccines and Gut Microbiome: a rational approach to optimize cancer immunotherapy)
Período documentado: 2024-03-01 hasta 2024-08-31
A growing body of evidence supports the notion that the gut microbiome plays an important role in cancer immunity. However, the underpinning mechanisms remain to be fully elucidated. Three mechanisms have been postulated. 1) The release of metabolites, such as polyamine, vitamin B16 and short chain fatty acids, which mediate systemic effect on the host. 2) The engagement of pattern recognition receptors (PRRs) that mediate pro-immune effects. For instance, it has been shown that TLRs and NOD2 ligands mediate the effect of E. hirae and B. fragilis. 3) The stimulation of cell-mediated immune responses against microbial antigens, which either provide help to tumor-specific immunity, or cross-react with tumor specific neo-epitopes (“Molecular Mimicry” (MM) hypothesis). This latter mechanism is particularly attractive since it would assign a previously unpredicted specificity to the anti-tumor activity of gut microbiome. However, the experimental evidence supporting the existence of cross-reactive epitopes was limited.
Scope of the Vaccibiome project was to demonstrate that MM play a relevant role in establishing tumor immunity.
We believe that the demonstration that MM is part of the mechanisms through which the gut microbiome contributes to cancer immunity is scientifically relevant. It brings an important contribution to our understanding of cancer biology and development. Moreover, it highlights how mammals and their microbiota have evolved together and how they have become inseparable companions for each other’s benefit. From a translational standpoint, MM could be exploited to design new anti-tumor prophylactic and therapeutic modalities based on the oral administration properly selected probiotics.
The main goal of the project was to experimentally demonstrate the role of MM in cancer immunity. To reach this goal two line of activities were followed both having as objective the demonstration that the microbiome is involved in the elicitation of T cells recognizing tumor epitopes homologous to microbial protein. First, commensal strains were engineered with cancer epitopes and the development of tumors expressing such epitopes was followed in mice that orally received the engineered bacteria. Second, we analysed whether the anti-tumorigenic activity of microbiome correlated with the presence of microbial endogenous proteins sharing homology to cancer-specific neo-epitopes.
Scope of the Vaccibiome project was to demonstrate that MM play a relevant role in establishing tumor immunity.
We believe that the demonstration that MM is part of the mechanisms through which the gut microbiome contributes to cancer immunity is scientifically relevant. It brings an important contribution to our understanding of cancer biology and development. Moreover, it highlights how mammals and their microbiota have evolved together and how they have become inseparable companions for each other’s benefit. From a translational standpoint, MM could be exploited to design new anti-tumor prophylactic and therapeutic modalities based on the oral administration properly selected probiotics.
The main goal of the project was to experimentally demonstrate the role of MM in cancer immunity. To reach this goal two line of activities were followed both having as objective the demonstration that the microbiome is involved in the elicitation of T cells recognizing tumor epitopes homologous to microbial protein. First, commensal strains were engineered with cancer epitopes and the development of tumors expressing such epitopes was followed in mice that orally received the engineered bacteria. Second, we analysed whether the anti-tumorigenic activity of microbiome correlated with the presence of microbial endogenous proteins sharing homology to cancer-specific neo-epitopes.
The human probiotic strains E. coli Nissle and Lactococcus lactis were successfully engineered with the MHC I epitope OVA. When administered to mice, the engineered strains were shown to elicit OVA specific T cells. Moreover, and importantly, if the animals were subsequently challenged with a tumor cell line expressing OVA the tumor growth was strongly inhibited. Since the engineered probiotic E. coli Nissle releases Outer Membrane Vesicles (OMVs), we also tested whether the OMVs could play a role in the elicitation of the epitope-specific T cells and in protection against tumor challenge. Indeed, the oral administration of OMVs carrying the OVA epitope promoted tumor inhibition in challenged animals. Importantly, we also demonstrated that OMVs decorated with MHC I epitopes other than OVA induced epitope-specific T cells, indicating that T cell production is a general property of intestinal OMVs. This is a particularly interesting result in that it sheds light on a new biological OMV function never reported before.
In a parallel study, we orally administered the probiotic Bifidobacterium and we found that the administration resulted in a perturbation of the intestinal flora. When mice were challenged with a tumor cell line, the animals appeared to be more resistant to tumor development. In line with the MM hypothesis, we discovered that such resistance was associated to the presence of new intestinal microbial species, which carried proteins homologous to immunogenic epitopes present in the tumor cells.
The results of the Vaccibiome project described above, as well as other related data generated thanks to the Vaccibiome financial support, were made publicly available through five publications in international, peer-reviewed, journals and also but oral communications at conferences and seminars at which the PI of the project participated as invited speaker. Other publications will be submitted soon.
The translational value of the project can be appreciated by the fact that a Proof-of-Concept ERC Grant (INSITUOMVAC) was assigned to the PI of the project in June 2023 and the PI is currently looking for additional funding to bring a novel OMV-based immunotherapeutic formulation to development.
In a parallel study, we orally administered the probiotic Bifidobacterium and we found that the administration resulted in a perturbation of the intestinal flora. When mice were challenged with a tumor cell line, the animals appeared to be more resistant to tumor development. In line with the MM hypothesis, we discovered that such resistance was associated to the presence of new intestinal microbial species, which carried proteins homologous to immunogenic epitopes present in the tumor cells.
The results of the Vaccibiome project described above, as well as other related data generated thanks to the Vaccibiome financial support, were made publicly available through five publications in international, peer-reviewed, journals and also but oral communications at conferences and seminars at which the PI of the project participated as invited speaker. Other publications will be submitted soon.
The translational value of the project can be appreciated by the fact that a Proof-of-Concept ERC Grant (INSITUOMVAC) was assigned to the PI of the project in June 2023 and the PI is currently looking for additional funding to bring a novel OMV-based immunotherapeutic formulation to development.
We believe that the scientific and translational relevance of this work is threefold. First, it provides additional experimental evidence on the influence of microbiome-induced T cell immunity in tumor progression. While microbiome can exert anti-tumorigenic effects through other mechanisms, the “fortuitous” elicitation of cytotoxic T cells cross-reacting with immunogenic tumor-specific neoepitopes is here experimentally demonstrated. Second, this work uncovers a novel biological function of OMVs, which extends to cancer immunity. The capacity of microbiome-release vesicles to contribute to tumor inhibition further underlines how inseparable evolution has made mammals and their microbiota. Finally, this work suggests a new approach of personalized cancer immunotherapy whereby probiotic bacteria and/or their OMVs are delivered orally once engineered with properly selected tumor-specific T cell epitopes.