Bacterial metabolites and immunotherapy effectiveness
It is not so much the intestinal bacterial species as their metabolic pathways that determine the effectiveness of immunotherapy in cancer treatment. Could this pave the way for therapies combining immunotherapy and biotics?
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About this article
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Immune checkpoint inhibitors (ICIs)
Therapies that seek to remove the mechanisms that inhibit the immune system’s response to cancer cells. Targeted checkpoints include Programmed Death-1 (PD-1), Programmed Death-Ligand 1 (PDL-1), and cytotoxic T-lymphocyte associated protein 4 (CTLA-4). Lifting these brakes allows the immune system to recognize and attack cancer cells.
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significantly improves cancer survival, but its effectiveness varies greatly from one patient to another. Studies have shown a link between certain gut bacteria and efficacy, but the species implicated are inconsistent from one study to another. What if it wasn't so much the species themselves as the metabolites they produce that made all the difference? This is the hypothesis, confirmed by a Dutch team1.
400 000 Each year, approximately 400 000 children develop cancer².
1/6 Cancer is a leading cause of death worldwide, accounting for nearly 10 million deaths in 2020, or nearly one in six deaths².
Bacterial species vary
Analysis of 781 fecal samples from cancer patients treated with ICB shows that bacterial species composition varies greatly between patients and between studies. Furthermore, bacterial diversity does not appear to be related to treatment response. Finally, the profile of the intestinal flora in terms of bacterial species does not allow for a clear distinction between responders and non-responders.
Top 6 (cases)²
The most common in 2020 (in terms of new cases of cancer) were:
- breast (2.26 million cases);
- lung (2.21 million cases);
- colon and rectum (1.93 million cases);
- prostate (1.41 million cases);
- skin (non-melanoma) (1.20 million cases); and
- stomach (1.09 million cases).
Metabolic dysbiosis is associated with poor prognosis
The results are quite different when we look at the metabolism of the gut microbiota rather than its bacterial composition. These functions are relatively stable between patients and between studies. Non-responders show more pronounced functional dysbiosis than responders. Furthermore, the closer the flora's metabolic profile is to that of a healthy control microbiota, the better the response to ICB.
These results are confirmed in a prospective cohort. Thus, an alteration in the metabolic functions of the gut microbiota appears to go hand in hand with a poor response to immunotherapy.
Top 5 (deaths)²
The most common causes of cancer death in 2020 were:
- lung (1.80 million deaths);
- colon and rectum (916 000 deaths);
- liver (830 000 deaths);
- stomach (769 000 deaths); and
- breast (685 000 deaths).
The pathways involved
Finally, the researchers identified various metabolic pathways involved in the response to treatment, including the methyl erythritol phosphate (MEP) pathway. This pathway, which is specific to bacteria, produces phosphoantigens (e.g., HMBPP) and activates Vδ2 lymphocytes involved in antitumor immunity. It is strongly associated with a better response to ICB in different types of cancer. The researchers provide mechanistic evidence: bacteria capable of producing HMBPP (an intermediate in the MEP pathway) stimulate the antitumor activity of Vδ2 T lymphocytes.
A reverse, inhibitory pathway has also been revealed: microbial production of riboflavin is associated with resistance to ICB, induces suppression of immunity mediated by another type of T lymphocyte (MAIT cells, Mucosal-Associated Invariant T cells) and is associated with lower survival rates.
Thus, the metabolic capacity of the microbiota appears to be a major determinant of response to ICB. Will understanding and modulating these microbial functions pave the way for new therapeutic interventions, combining microbiota and immunotherapy to improve the effectiveness of cancer treatments?
