What’s gut got to do with it? How the gut microbiome affects cancer immunotherapy

Bacteria are virtually everywhereon bus seats, on our hands, and even inside of our gutbut that isn’t necessarily a bad thing. These bacteria are part of the microbiome, the collection of microorganisms that live in or on an environment (such as the human body). The microbiome is thought to influence many aspects of human health, including metabolism and immune function. However, not all microbiomes are created equal. A recent study points to differences in the human gut microbiome as an associated factor in which melanoma patients respond to the cancer immunotherapy termed anti-PD-1 therapy.

Cancer immunotherapies aim to bolster the immune response to cancer cells. This is because the immune system plays an integral role in eliminating cancer cells, but cancer cells have ways of evading or preventing an immune response. One such tactic cancer cells use is through the PD-1 checkpoint.

During an immune response, white blood cells termed T-cells can detect and kill abnormal cells, such as cells infected with a virus or even cancer cells. At some point, such as when no more abnormal cells are around, the T-cells need to be told to stop attacking. T-cells have an “off-switch”, a receptor called PD-1, that binds to the PD-1 ligand (termed PD-L1). When these two bind, T-cells receive a signal to stop attacking. This is incredibly important to prevent autoimmunity in which T-cells attack normal cells. PD-L1 is normally expressed by immune cells and some other cell-types (including epithelial and endothelial cells) during an immune response. However, sometimes cancer cells hijack this function and shutdown T-cells that are rightly attacking the abnormal cancer cell.

Anti-PD-1 immunotherapy blocks PD-1:PD-L1 interaction, thus preventing the cancer cells from shutting down the immune response. It is an incredible advancement, but not all cancer patients respond to anti-PD-1 therapy. It is unclear why, but one suspect is the gut microbiome.

Previous research using a mouse model shows that the gut microbiome plays a role in whether or not mice respond to anti-PD-1 therapy. In the publication titled“Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients,” Gopalakrishnan et al. explore if this holds true for human melanoma patients.

In this study, participating patients provided cheek swabs to characterize the oral microbiome—as well as stool samples to characterize the gut microbiome—at timepoints before and after starting anti-PD-1 therapy. The subset of patients that responded to anti-PD-1 therapy were termed responders, while those who did not respond to anti-PD-1 therapy were termed non-responders.

The researchers noted a difference between responders and non-responders: the diversity of the gut microbiome and what species of bacteria comprised the gut microbiome. The oral microbiome did not have a significant influence on either group.

Responders tended to have higher diversity in gut bacteria, as well as a higher abundance of the bacterial species Faecalibacterium. In fact, patients with high Faecalibacterium abundance had prolonged progression-free survival compared to patients with low Faecalibacterium abundance. Additionally, the metabolic activity of responders’ gut microbiome was predominately enriched for anabolic functions.

Conversely, non-responders tended to have lower diversity in gut bacteria and a higher abundance of bacteria of the order Bacteroidales. Patients with high Bacteroidales abundance had shortened progression-free survival compared to patients with low Bacteroidales abundance. The metabolic activity of non-responders’ gut microbiome were enriched in catabolic functions.

Does this association actually mean the bacteria had anything to do with response to PD-1 inhibition?

To investigate a causal link, Gopalakrishnan et al. performed fecal microbiota transplant (FMT) experiments, in which the fecal microbiome of responders or non-responders were transplanted into germ-free mice. They injected melanoma cells into mice, and then monitored tumor formation. Mice which received FMT from responders had decreased tumor size compared to non-responder FMT recipient mice. Additionally, responder-FMT recipient mice had improved response to anti-PD-L1 therapy compared to non-responder-FMT recipient mice. The responder-FMT mice also had increased immune infiltration into tumors than non-responder-FMT mice, another indication of increased anti-PD-L1 therapy efficacy.

So, what do gut bacteria have to do with melanoma patients’ response to anti-PD-1 therapy? These data suggest there is an association between gut microbiome and anti-PD-1 therapy response, though the exact mechanism behind this role is unclear. Future studies are required before researchers can definitively say how bacteria such as Faecalibacterium affect anti-PD-1 therapy efficacy. As the knowledge of the microbiome grows, it will continue to open up new opportunities to better understand human health.

Reference:
Gopalakrishnan, V. et al. Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients. Science. 2018 Jan 5;359(6371):97-103. DOI: 10.1126/science.aan4236

Featured Image:
Darryl Leja via NIH Image Gallery CC BY-NC 2.0

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