A Sheep in Wolf’s Clothing: Mimicking Tumor with Probiotic

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Take a look in the mirror. What do you see?

Given that you are reading an immunology blog, I hope your answer would be something along the line of a human being, or Homo sapiens if you want to be fancy.

Now, let’s take a closer look together!

At the genetic level, humans consist of approximately 22,000 genes. On the other hand, the bacterial community all over our body has approximately 8 million unique genes. Just like the plethora of living organisms on Earth, particular bacteria often have a preferred niche within our body.

Commensal bacteria have co-evolved with their human host over thousands of years, and play an important role in host’s wellbeing. For instance, some gut microbes produce molecules such as vitamin B16, polyamines, and short-chain fatty acids that are important for host immunity. In addition to nutrient absorption, the gastrointestinal tract also serves as an important contact point for the commensal microbes and host immune cells. During these interactions, the adaptive immune cells, B and T cells, learn to recognize the appearance of the microbes in case they ever try to slip across the gastrointestinal border. 

Molecular Mimicry Can be a Double-Edged Sword

The commensal bacteria population is enormous and diverse. By random chance, some of these bacteria may have components, known as epitopes, that resemble other bacteria, viruses, or even allergens. As a result, the adaptive immune cells can acquire cross-reactivity to other similar epitopes as they learn to recognize the commensal bacteria. This phenomenon – known as molecular mimicry – can act as a double-edged sword. When the bacterial antigen resembles a pathogen component, the mimicry would strengthen immune defenses. On the other hand, mimicry of harmless allergens may lead to life-threatening allergic reactions.

If the bacterial epitopes can mimic viruses or allergens, it would not be surprising for them to mimic human antigens, including that found in cancer cells. Indeed, numerous studies have demonstrated the connection between gut bacteria and cancer immunity, but the mechanism remains unclear. Therefore, Tomasi and colleagues sought to evaluate the role of molecular mimicry in tumor immunity so we can harness the commensal bacteria in cancer treatment.

Engineering Cancer-Mimicking Probiotic

To test the molecular mimicry hypothesis, Tomasi and colleagues engineered the probiotic bacteria, E. coli Nissle 1917 (EcN), to express an ovalbumin epitope (OVA). Ovalbumin is the main protein found in egg whites and is often used as a cost-effective antigen in immunology research. When the OVA epitope is expressed on EcN, it is tethered to an outer membrane-associated Braun’s lipoprotein (Lpp) so that it can be detected by immune cells. When these engineered bacteria (abbreviated as EcN-OVA) are administered to mice orally, mice develop OVA-specific CD8⁺ T cells in their small intestine. To artificially create the molecular mimicry between bacterial epitopes and tumors, the researchers tested the effect of EcN-OVA on mice that have OVA-expressing melanoma cells. Given that both the bacteria and cancer express OVA, the CD8⁺ T cells elicited by EcN-OVA will recognize cancer as well! Consequently, the EcN-OVA reduced the tumor development in treated mice!

            Interestingly, as a Gram-negative bacterium, EcN also releases outer membrane vesicles (OMVs), which are tiny spheres that carry bacterial cargoes. Given the small size of these vesicles, they can easily cross the intestinal barrier and come in contact with immune cells. Thus it appears plausible that they may contribute to the anti-tumor activity from the EcN-OVA. Indeed, the western blot confirmed that the OVA epitopes are found on these OMVs. Furthermore, the researchers found that purified OMVs from the EcN-OVA alone also delayed the growth of OVA-expressing melanoma cells.

Cancer-Mimicking Probiotic Induces Anti-Tumor Immunity

            As a finishing touch to their new discovery, the researchers isolated the tumors from mice treated with EcN-OVA and the OMVs and measured over 2-fold increase of OVA-specific CD8⁺ T cells and a 3-fold reduction in the immunosuppressive T regulatory cells (Tregs). Together, these two changes synergistically enhance the tumor-killing activity in EcN-OVA/OVA-treated mice.

            To recap, Tomasi and colleagues demonstrated that molecular mimicry of tumor antigens can redirect the immune system against tumors. Therefore, it is conceivable to design personalized probiotics that mimic the tumor antigen of the patient to train tumor specific CD8⁺ T cells. This study serves as a great proof of concept for utilizing genetically engineered probiotics to fight cancer in the future.

Source:

Tomasi M, Caproni E, Benedet M, Zanella I, Giorgetta S, Dalsass M, König E, Gagliardi A, Fantappiè L, Berti A, Tamburini S, Croia L, Di Lascio G, Bellini E, Valensin S, Licata G, Sebastiani G, Dotta F, Armanini F, Cumbo F, Asnicar F, Blanco-Mı´guez A, Ruggiero E, Segata N, Grandi G and Grandi A (2022) Outer Membrane Vesicles From the Gut Microbiome Contribute to Tumor Immunity by Eliciting Cross-Reactive T Cells. Front. Oncol. 12:912639. doi: 10.3389/fonc.2022.912639

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