Periodic Reporting for period 3 - VACCIBIOME (Cancer Vaccines and Gut Microbiome: a rational approach to optimize cancer immunotherapy)
Período documentado: 2022-09-01 hasta 2024-02-29
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. One attractive hypothesis envisages that microbiome proteins elicit immune cells (T cells) which recognize neo-epitopes arising from cancer mutations (“molecular mimicry (MM)” hypothesis). The demonstration of the role of MM would bring an important contribution to our understanding of cancer immunity and would highlight how inseparable evolution has made mammals and their microbiota. Moreover, MM could be exploited to design new anti-tumor prophylactic and therapeutic modalities based on the oral administration properly selected probiotics.
To demonstrate the role of MM, human probiotic strains were engineered with an immunogenic epitope expressed in a tumor cell line. The engineered strains were administered to mice and the animals were subsequently challenged with tumor cells expressing the selected epitope. The data show that not only the probiotic strains elicited epitope-specific T cells, but also that the treated animals were protected from tumor growth. Since the engineered probiotic strains release Outer Membrane Vesicles (OMVs) we also tested whether the released OMVs could be responsible for the induction of the epitope-specific T cells and for protection against tumor challenge. Indeed, the oral administration of OMVs promoted tumor inhibition in challenged animals. This is a particularly interesting result in that it sheds light of a new biological OMV function. In a parallel study we also altered the gut microbiome and subsequently mice were challenged with a syngeneic tumor. The results indicate that mice with the modified microbiome were more resistant to tumor development and such resistance appeared to be associated to the presence of new intestinal microbial species which carried proteins homologous to immunogenic epitopes present in the syngeneic tumor cells.
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. From now to the end of the project our objective is to provide additional experimental evidence of the role of molecular mimicry. Different mouse tumor models will be tested and different therapeutic and prophylactic modalities will be explored.