Federica Spaggiari MicrobiotaMi

MicrobiotaMi Comment 28_21  by Federica Spaggiari

Related Journal Article:  Identification of bacteria-derived HLA-bound peptides in melanoma

This article was published in the: Nature 592, 138–143 (2021). https://doi.org/10.1038/s41586-021-03368-8

Bacteria-derived peptides are presented by HLA molecules in melanoma

A large amount of bacteria colonize healthy mucosal tissue of the human body from early life and create a symbiotic relationship with the host organism. The commensal flora composition varies between individuals and life stages. More recently, tumour-resident bacteria has captured the attention of the scientific community. Indeed, multiple studies are focused on understanding the role of specific microbial populations within tumoral masses and on the discovery of a correlation between bacteria colonization and cancer progression or response to treatments.

In their work, Kalaora et al. aimed to describe the bacteria population of melanoma and understand whether bacterial antigens are presented by HLA-molecules. Thus, the group performed 16S rRNA sequencing analyses on tissue derived from melanoma metastases. Interestingly, they managed to describe a conserved bacteria population among samples collected from both the same or different patients. The taxonomic profiling of whole-genome sequencing dataset of melanoma on both tumor and blood samples highlighted that the former’s microbiota richness is higher and that some species seem to be specifically tumour enriched.

To evaluate the entire set of peptides presented by HLA-I and HLA-II molecules, they performed HLA peptidome analysis on the same tumour samples. The analysis allowed the identification of peptides exclusively bound by HLA-I or HLA-II. Among the HLA-I-specific peptides, 11 were derived from Fusobacterium nucleatum, Staphylococcus aureus and Staphylococcus capitis. Bacteria-derived peptides shared common characteristics. Indeed, they were highly hydrophobic and, consequently, more suitable for antigen presentation and T cell recognition.

In order to merge the evidence collected from the 16S sequencing and the peptidomics analysis, the ability of the identified bacteria to enter melanoma cells was demonstrated by cocultures of melanoma cells and different bacterial strains and immunofluorescence staining. After confirming the bacterial capacity of accessing tumour-derived cells, the same cell cultures were exploited for peptidomics analysis. Interestingly, previously identified HLA-bound peptides could be detected in cells co cultured with bacteria, in particular with the most aggressive ones, such as Fusobacterium nucleatum and Staphylococcus caprae.

Bacteria directly isolated from tumours were used to perform the aforementioned experiments. As expected, the isolated microbes could penetrate melanoma cells which, in turn, presented  the peptides identified with peptidomics studies on HLA-molecules. Among all the detected peptides, the majority of them derived from pyruvate-ferrodoxin (flavodoxin), produced by Fusobacterium nucleatum.

Since antigen-presentation is fundamental for T cell activation, such bacterial antigen presentation gives intratumoral bacteria a pivotal role in the dynamics of the host immune response to cancer. The reactivity of tumour infiltrating antigens isolated from melanoma samples against HLA-I-bound bacterial peptides was tested. Co culture of transformed B cells expressing bacterial antigens and TILs caused a significant increase in the latter production of INFɣ. Conversely, the interaction with normal B cells does not elicit such a strong response.

This study is an additional proof of the multifaceted activity of bacteria within the host organism in both healthy and diseased state. Indeed, it underlines the importance of the tumour-resident microbiota and its central role in modulating tumoural immune response. So far, anti-cancer therapies strategies have been focused on finding targets among the host-specific ones. What has been observed by Kalaora et al. could bring a change of perspective and to the development of alternative therapeutic approaches that take into consideration the active role in antigen presentation of bacteria residing in the tumour.

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