Monday Article #64: Using skin-dwelling bacteria to fight cancer
Similar to those seen in our gut, our skin also harbours millions of bacteria, viruses, and fungi to form the skin microbiota. These microorganisms live in harmony with humans without causing harm to our health. However, several bacterial species found on the skin, such as Staphylococcus epidermidis, can stimulate a highly specific T cell immune response, where the underlying mechanism is still not well defined. Utilising this, Chen et al. (2023) engineered S. epidermidis to fight against melanoma, a type of skin cancer derived from melanin-forming cells (melanocytes).
Figure 1. Staphylococcus epidermis, a skin-dwelling bacteria (Uribe-Alvarez et al., 2016).
The T cell-mediated immune response
T cells originate from progenitor cells in the bone marrow, then migrate to the thymus for maturation and selection (Kumar, Connors, and Farber, 2018). After they complete their development in the thymus, they are then carried through the bloodstream to peripheral lymphoid organs. These naïve T cells (T cells that have not yet encountered their antigen) then recirculate between the bloodstream and peripheral lymphoid tissues until they encounter their specific antigen. When a pathogen invades the body, cells such as macrophages and dendritic cells will engulf these microorganisms and break them down. The foreign antigen will then be loaded onto a major histocompatibility complex (MHC) to be presented on their surfaces, hence, these cells are known as antigen-presenting cells.
Naïve T cells are able to recognize their antigen through interaction with a peptide-MHC complex found on the surface of these antigen-presenting cells. Once these naïve T cells have encountered their antigen, they will then proliferate and differentiate into effector T cells, which are able to participate in an immune response to aid in the removal of that invading antigen.
Engineering of Staphylococcus epidermidis to fight against cancer
Usually, when an infection occurs, CD8 T cells will be activated to attack and destroy the target cells that display the specific antigen. However, in the case of Staphylococcus epidermidis, the S. epidermidis-targeting T cells formed do not act against these antigen-bearing target cells, but instead idle around the body. Chen and his colleagues realised that perhaps changing the target of these CD8 T cells could put them into action, which was what they did in their research.
Chen and his team engineered a S. epidermidis to express a melanoma tumour antigen, ovalbumin, instead of their usual ones. Following that, live engineered S. epidermidis, killed engineered S. epidermidis, a wild-type version of the bacteria, or no bacteria at all, were swabbed onto mice. The mice were then injected with ovalbumin-expressing melanoma cells six days after the swab. All mice that were swabbed with killed, wild-type, or no bacteria rapidly developed skin tumours, while those who received live engineered bacteria had either no growth of tumours at all, or slowed tumour growth. This shows that the CD8 T cells formed against the engineered S. epidermidis were successfully activated and spread throughout the body to destroy the cancerous cells. Therefore, engineered S. epidermidis has potential for the development of vaccines against melanoma.
Besides that, another group of mice were also injected with cancer cells two weeks prior to swabbing with engineered bacteria to test if the engineered S. epidermidis could act as a treatment for established cancer. It was found that the CD8 T cells were able to target the cancer cells to shrink or eliminate them, thus increasing survival time. Combination of the engineered bacteria with a booster of T cell activity displayed outstanding results, where 15 out of 16 tumours were eliminated from the mice. Furthermore, upon re-injection of the mice with cancer cells 30 days later, tumour growth was successfully prevented in the mice, suggesting the presence of an immunological memory.
Conclusion and future perspectives
Despite the exceptional results obtained from this research, this method of treatment has only been tested on mice so far, posing questions as to whether this would be effective for humans. However, if this therapeutic method could be applied for the treatment and prevention of cancer, it would provide an economical and non-invasive treatment option for cancer due to the abundance of skin-dwelling bacteria and application of the treatment onto the skin surface.
References
Chen, Y.E., Bousbaine, D., Veinbachs, A., Atabakhsh, K., Dimas, A., Yu, V.K., Zhao, A., Enright, N.J., Nagashima, K., Belkaid, Y. and Fischbach, M.A. (2023) ‘Engineered skin bacteria induce antitumor T cell responses against melanoma’, Science, 380(6641), pp.203-210. [Online] DOI: 10.1126/science.abp956
Uribe-Alvarez, C., Chiquete-Félix, N., Contreras-Zentella, M., Guerrero-Castillo, S., Peña, A. and Uribe-Carvajal, S. (2016) ‘Staphylococcus epidermidis: metabolic adaptation and biofilm formation in response to different oxygen concentrations’, FEMS Pathogens and Disease, 74(1), p.ftv111. [Online] DOI: 10.1093/femspd/ftv111
Kumar, B.V., Connors, T.J. and Farber, D.L. (2018) ‘Human T cell development, localization, and function throughout life’, Immunity, 48(2), pp.202-213. [Online] DOI: 10.1016/j.immuni.2018.01.007
This article was prepared by Phoebe Tee