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Anthony Tao
Bacteria are not often given the respect they sometimes deserve. People tend to consider them as foreign harbingers of plagues, colds, and rashes ‒ unwanted invaders that our immune systems are uniquely tasked to deport. Of course, it is very well accepted now that many of these microbes indeed carry anatomic citizenship, ranging from our guts to our lungs to our skins. And what’s more, these residents have been shown to positively impact important processes occurring within our body, including supporting our immune system.
The population of bacteria that are naturalized in our body is known as the microbiome. The gut microbiome is perhaps the most popularly studied among immunologists and has well-defined roles in helping food digestion, training immune cells, and even modulating cancer treatment. However, the microbiome of tumors and how it influences tumor growth is less understood. This is especially true when it comes to how tumor-resident bacteria can influence anti-tumor immunity.
In a recent paper from Navhavian et al. (2023), a group from the University of Zurich attempted to address this gap in knowledge by characterizing the bacterial proteins that are presented to T cells, which can coerce a T cell-mediated attack on the cancer cells, specifically glioblastoma, an aggressive form of brain cancer.
Antigen presentation refers to a process by which specialized cells help the T cells recognize proteins, or antigens, belonging to harmful bacteria or cancer cells, licensing T cells to attack them. In a typical immune response to a foreign attack, the first responders are usually antigen-presenting cells, which can eat the foreign bacteria and hold out pieces of the bacterial proteins (called peptides) on specialized proteins known as major histocompatibility complexes (MHC). The right T cells can then recognize the peptide and launch an assault against the invader. Without antigen presentation, T cells are blind.
It is also important to note that every T cell is designed to be unique. In cancer, only a tiny percentage of the millions of T cells in our immune system can recognize a specific tumor antigen. Generally, no two T cells in our body recognize the exact same antigen. A specific T cell with its antigen (or antigens) of choice is referred to as a T cell clone. This gives our immune system the flexibility to respond to a wide variety of foreign antigens out in the world that can potentially invade our bodies. However, cross-reactivity can occur, in which multiple antigens are recognized by the same T cell clone.
In cancer, cells within the tumor use their MHC proteins to capture and present cancer antigens, allowing T cells to recognize and eliminate tumor cells. However, whether these antigen-presenting cells can also present bacterial antigens is not well-described, especially in glioblastoma.
To address this question, the researchers from Zurich extracted MHC molecules from resected glioblastomas directly from patients to identify what peptidesーthat is, what fragments of full proteinsーwere being presented through these MHCs. This was accomplished by a technique known as mass spectrometry, which allows scientists to simultaneously quantify the mass of hundreds to thousands peptides and thereby, their unique identities. Interestingly, in all samples, they found a variety of bacterial peptides, indicating that the bugs of the tumor microbiome are indeed being presented to T cells. This finding hints at the idea that not only do bacteria exist within glioblastoma, but they may be actively involved in modulating anti-tumor immunity.
To address this possibility, the scientists next wanted to know if presentation of bacterial peptides could directly activate the anti-tumor function of T cells present in the tumors ‒ also known as tumor-infiltrating lymphocytes (TILs). To do this, they artificially synthesized these peptides and loaded them onto MHC molecules, which they then used to stimulate TILs, taken directly from the patient glioblastoma samples. They found that presentation of these peptides was capable of inducing T cells to proliferate and secrete pro-inflammatory signaling molecules, functions which are necessary for their anti-tumor effects.
These findings suggest that bacteria housed in the tumor can be presented to T cells and may aid in the anti-tumor response. By testing specific T cell clones, the scientists also show evidence that the ability of these T cells to recognize bacteria may, in some part, be a result of cross-reactivity. In other words, these T cells were brought into the tumor because of their ability to recognize tumor antigens; yet, the presence of bacterial antigens might further boost their activity. Whether some T cell clones were brought in due to their specific recognition of bacteria is not known.
To further evaluate the extent of this cross-reactivity, the scientists narrowed their focus to one T cell clone that strongly recognizes a glioblastoma-specific antigen. T cells recognize unique antigens due to the specific amino acid sequences that make up the antigen. The researchers performed a technique known as positional scanning, allowing them to experimentally determine which amino acids at which positions of a peptide best activate the T cell clone. Ultimately, given a database of amino acid sequences from millions to billions of bacterial peptides, this information could be used to computationally predict if any known bacterial antigens can be recognized by the T cell clone.
The researchers then synthesized these predicted bacterial antigens and tested them against the T cell clone. Excitingly, many were found to induce strong anti-tumor responses. These predicted bacterial antigens were also capable of cross-reacting with other T cell clones. This suggests that in general, some T cells specialized for recognizing glioblastoma can also recognize and be influenced by the presence of bacteria in the tumor.
Overall, the scientists illustrate a model in which anti-tumor T cells can be boosted by the presence of the bacteria within glioblastoma, primarily through the presentation of bacterial antigens on specialized antigen-presenting cells. The question remains as to how this phenomenon can be leveraged in cancer therapy or diagnosis. One can envision a world in which specific bacteria are mixed with existing therapies to enhance tumor eradication by T cells. As crazy as it sounds, this is not a new idea. In fact, the inception of this concept first flickered back in the 1800s, albeit crudely, when the American surgeon William Coley treated bone cancer by injecting bacteria directly into them.
However, it is important to realize that the relationship between a tumor and its microbiome is far from simple. Like voters of a multicultural state defined by a vast diversity of opinions and backgrounds, different bacterial strains can have both pro-tumor and anti-tumor roles, depending on cancer type and progress. More studies that attempt to broadly characterize the intersectionality between tumor-resident bacteria and immune cells will be crucial in establishing a microbiome-literate approach when it comes to clinical oncology.
Edited by Charlotte Boyd
Cover photo. Generated by DALLE-2
References
1. Naghavian, R. et al. Microbial peptides activate tumour-infiltrating lymphocytes in glioblastoma. Nature 617, 807–817 (2023).
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