Did you know that some harmless bacteria still produce a potent immune response? The immune response produced by these commensal bacteria was harnessed by a team of researchers by engineering a common skin bacteria to express cancer antigens. The resulting T cells produced when this bacteria colonized the skin of mice with subcutaneous melanoma were able to slow tumor growth, even in aggressive cancers. This finding opens up an entire new area for the development of cancer therapeutics.
What is Commensalism?
When people talk about the human microbiome, they are almost always not referring to the bacteria and viruses that make us sick, but to the ‘good’ species of microorganisms we live with. These are the bacteria, viruses, and fungi that are supposed to be present in and on the human body. It is increasingly known that these commensal microbiota do not only coexist with humans, but play important roles in immunity, digestion, transplant recovery, and more.
One unusual feature of some species of commensal bacteria is a potent, specific immune response induced in the absence of infection. This means that merely by colonizing a tissue in a harmless way, the bacteria can induce T cell activation. The T cells express T cell receptors (TCRs) that are highly specific to the bacterial colonist, like in an infection, but none of the inflammatory processes associated with infection are activated.
Harnessing Anti-Commensal Immunity
A team of researchers at Stanford Medicine and a colleague were curious about this strange biological phenomenon. Could these colonist-induced T cells behave in the same important, infection-clearing ways as other immune cells? If so, can this ‘anti-commensal immunity’ be harnessed and redirected at a target of interest?
The answers turned out to be ‘yes.’ In a recent paper published in Science, the team described an approach to answer both questions at the same time. The authors engineered a strain of bacteria that normally colonizes the skin, Staphylococcus epidermidis, to express tumor antigens. By colonizing the skin of mice with the engineered bacteria, they could induce T cells using anti-commensal immunity and see if those T cells were capable of leaving the initial tissue type, infiltrating a tumor, and killing tumor cells.
Engineered Skin Bacteria as Melanoma Immunotherapy
S. epidermidis is commonly found on healthy human skin, and has the ability to elicit CD4+ and CD8+ T cell responses in mice and non-human primates as well as humans. Multiple strains of this bacteria were engineered to contain ‘model’ or common cancer antigens as well as ‘neoantigens,’ or antigens that are unique to a given tumor. Mice were injected with a cancerous cell line to induce subcutaneous melanoma, and their skin was swabbed either with no bacteria, with control bacteria (engineered to express a harmless protein), or with the bacteria engineered to express the cancer antigens.
The engineered bacteria did indeed induce tumor-specific CD4+ and CD8+ T cells after colonizing the skin. Better still, these T cells could migrate from the colonization site to other skin sites and even the lungs, exhibiting strong antitumor activity when they got there and dramatically slowing the growth of even aggressive and metastatic melanoma. The authors note that the bacteria must be alive to induce the immune response, suggesting that it is something about the active process of colonization that may stimulate the immune system.
This is a true feat of bioengineering. Engineered commensal colonists provide not only a way to generate antigen-specific T cells against a target of interest like a tumor, but since the body makes the T cells itself, there is no need for an additional delivery vector. In addition, the T cells work extremely well in combination with immune checkpoint inhibitors (ICIs), some of the most effective cancer treatments currently available. In a melanoma subtype that doesn’t respond to immune checkpoint inhibitors alone, the combination of ICIs and engineered bacteria led the mice to reject 15 out of 16 induced tumors.
This paper’s findings propose tremendous potential for the development of engineered commensal bacteria as therapeutic agents, and human clinical trials will show if this approach can translate to become a powerful tool for fighting cancer.
Outsourcing Bioinformatics Analysis: How Bridge Informatics Can Help
Groundbreaking studies like these incorporating genetic engineering and complex data analysis are made possible by technological advances making biological data generation, storage and analysis faster and more accessible than ever before. From pipeline development and software engineering to deploying existing bioinformatics tools, Bridge Informatics can help you on every step of your research journey.
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Jane Cook, Biochemist & Content Writer, Bridge Informatics
Jane Cook, the leading Content Writer for Bridge Informatics, has written over 100 articles on the latest topics and trends for the bioinformatics community. Jane’s broad and deep interdisciplinary molecular biology experience spans developing biochemistry assays to genomics. Prior to joining Bridge, Jane held research assistant roles in biochemistry research labs across a variety of therapeutic areas. While obtaining her B.A. in Biochemistry from Trinity College in Dublin, Ireland, Jane also studied journalism at New York University’s Arthur L. Carter Journalism Institute. As a native Texan, she embraces any challenge that comes her way. Jane hails from Dallas but returns to Ireland any and every chance she gets. If you’re interested in reaching out, please email [email protected] or [email protected].