Introduction
The human gastrointestinal tract is colonized by approximately 10
14 microbes equating to roughly 1000 times the number of cells and 10,000 times the DNA content of the human body [
1].
Gut microbiota include several species of microorganisms but the
Firmicutes and
Bacteroidetes phyla account for 90% of the total [
2].
In addition, type of delivery [
3], methods of milk feeding [
4] and weaning period [
5] have a major impact on the microbiota composition in the first year of life.
The child’s gut microbiota composition and diversity reaches the adulthood characteristics at approximately three years of age as consequence of genetics, environment, diet, lifestyle, and gut physiology [
6]. Several factors may induce variations in the gut microbiota during the life, including lifestyle, dietary and cultural habits [
7].
Gut bacteria regulate food digestion along the gastrointestinal tract and prevent bacteria invasion by maintaining the intestinal epithelium integrity [
8]. In addition, they have been shown to regulate the development, homeostasis, and function of innate and adaptive immunity [
9].
Besides the physiological role, the microbiota have a role in human diseases [
10,
11] and influence both tumor development and treatment response [
12‐
19]. In particular, specific microbiota populations have been show to affect cancer genesis and development via the production of selected metabolites [
20]. Indeed, while components such as LPS or MPL activate T cell-mediated anti-cancer responses [
21], the bacterial virulence factor Fap2 can inhibit Natural Killers [
22]. Moreover, the polysaccharide A and TLR signaling to dendritic cells may drive the Tregs development [
23,
24] as well as segmented filamentous bacteria (SFB) may induce Th17 cells [
25].
In addition to such “generic” mechanisms of modulation, the impact of the gut microbiota on the anti-cancer immune response can be driven by a “molecular mimicry” between bacteria and tumor associated antigens.
The gut microbiome encodes over 3 million genes as whole, whereas the entire human genome consists of approximately 23,000 genes [
7]. Therefore, the probability of homology between microbiota and human antigens is high, resulting in an overlapping peptidome representation. Highly similar epitopes can be targeted by the same CD8
+ T cell receptor (TCR), given that a single TCR is cross-reactive recognizing at least 10
6 different MHC-bound peptides [
26,
27]. Indeed, the epitope binds to the HLA molecule with specific residues in fixed positions along the sequence (anchor residues) and only the central residues are exposed for recognition by the TCR (
http://www.cbs.dtu.dk/services/NetMHC/logos.php) [
28,
29]. Therefore, two unrelated antigens sharing the same TCR-facing central residues, or showing conservative variations at those positions, are very likely recognized by the same TCRs if the structural conformation of the entire epitope is saved.
Based on this assumption, we have recently shown that TAAs (
https://caped.icp.ucl.ac.be/Peptide/list) share sequence homology to viral sequences [
30]. This would suggest that viral antigens might elicit memory CD8
+ T cells cross-reacting with tumor antigens, able to control the growth of a cancer lesion, if expressing a TAA similar to the viral epitope. This may ultimately represent a relevant selective advantage for cancer patients and may lead to a novel preventive anti-cancer vaccine strategy [
31‐
33].
Here we report that significant sequence and conformational homology do exist also between TAAs and peptides derived from microbiota species of the Firmicutes and Bacteroidetes phyla. This suggests a much broader molecular mimicry between cancer and pathogens antigens with high potential cross-reactive T cell response and impact on tumor progression.
Discussion
The data reported in the present study show for the first time the high homology in the linear sequence as well as in structure and conformation between TAAs and peptides derived from microbiota species of the Firmicutes and the Bacteriodetes phyla, which together account for 90% of gut microbiota.
The number of homologous peptides with high affinity (< 10 nM) to HLA-A*02:01 molecule indicates that the molecular mimicry between TAA and microbiota-derived epitopes is not anecdotal and suggest a potential relevance in cross-reacting T cell response. In particular, about 70% of the paired epitopes show 6–7 identical residues along the 9-aa peptide sequence, 7% of them shows 8 identical residues and three of them show an identical sequence. Such long stretches of identical amino acids in a nonamer sequence suggest a great biological relevance given that a random event of an identical stretch of 6–9 amino acid in a nonamer sequence has an extremely low probability to occur (1.56 × 10–8–1.95 × 10–12). To further confirm the biological relevance of such a molecular mimicry, the consensus of the microbiota-derived epitopes always perfectly matches with the sequence of the corresponding TAA frequent residues. Moreover, the amino acid substitutions at each position are mostly conservative, confirming that the replacement does not significantly impact on the charge and conformation of the peptide structure.
The average predicted affinity of the microbiota-derived epitopes to the HLA-A molecules is extremely high, especially for the HLA-A*02:01 molecule (< 100 nm) and in about 50% of cases this is even higher than the corresponding TAA. According to our previous studies, such affinity values have a 100% correspondence to experimentally validated binding to HLA molecules. Therefore, this supports the concept that such microbiota-derived epitopes are indeed efficiently presented on the surface of cells to elicit a T cell response. Finally, the structural conformation of the microbiota-derived epitopes is, in general, highly similar to the corresponding TAA. In some cases, it is identical and contact areas with both HLA and TCR chains are indistinguishable. The spatial conformation of TCR-facing residues can be identical in paired TAA and microbiota-derived epitopes, with exactly the same values of planar as well as dihedral angles. This confirms that specific amino acid substitutions in the linear sequence do not affect the peptides structure and conformation which can be recognized by cross-reacting T cells. In support to this hypothesis, we have recently shown that CD8
+ T cells cross-react with TAAs and peptides derived from viruses, sharing the same level of homology observed in the present study [
24].
The biological relevance of the findings herein described is that, depending on the stage of the human life when the individuals will encounter the microbiota species, such homology may represent a favorable or unfavorable factor. Indeed, if the microbiota species have colonized the gastrointestinal tract in the first few months of life, the immune system could recognize the derived peptides as self-antigens and the specific T cell clones would be removed. In this case, a tumor lesion presenting a homologous TAA would have a selective advantage for establishing and progressing with a poor prognosis.
On the contrary, if the microbiota species have colonized the gastrointestinal tract later during life, the immune system could recognize the derived peptides as non-self-antigens and specific memory T cell clones would be established. In this case, as for a preventive vaccine, a tumor lesion presenting a homologous TAA would promptly recall the memory T cells able to eliminate or control tumor growth with an improved prognosis.
The relevance of our findings resides in the fact that the microbiota-derived antigens show homology with TAAs shared by several cancers of different histological origin. In particular, MAGE-A3 and MAGE-A10 have been identified in non-small cell lung cancers (NSCLC), bladder cancers, esophageal and head and neck cancers, and sarcomas [
34]. In particular, MAGE-A3 is over-expressed in multiple tumor types including melanoma [
35] and lung cancer [
36] and its presence has been associated with worse prognosis in colorectal cancer [
37], cutaneous squamous cell carcinoma [
38], and undifferentiated pleomorphic sarcoma/myxofibrosarcoma [
39]. Consequently, structural and conformational homology of peptides derived from microbiota species with these TAAs may have a strong impact on several cancers.
These findings open a new horizon in the mutual interaction between the microbiota and immune response in humans with a potential profound impact on tumor development and progression. Moreover, they provide a completely novel class of antigens to be possibly used as anti-cancer preventive vaccination, even administered as food integrators.
If confirmed, this would completely revolutionize the cancer immunotherapy field and represent a milestone in fighting cancer.
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