The Microbiome’s Influence on Immunotherapy

By: Gene Yang ‘19

Figure 1. E. coli is one of the many species of bacteria that live in the digestive tracks of humans and other animals. Collectively, these microbes make up the body’s gut microbiota.

Figure 1. E. coli is one of the many species of bacteria that live in the digestive tracks of humans and other animals. Collectively, these microbes make up the body’s gut microbiota.

When it was discovered that cancer cells with the protein PD-L1 avoid detection by the immune system, clinical trials involving PD-L1-targeted drugs emerged. These drugs, part of a class known as immune checkpoint inhibitors, block the interaction between the cancer cells’ PD-L1 protein and the immune system’s T cells, which then allows the immune system to detect and attack the tumor. Today, although treatment outcomes for specific cancer patients who respond to PD-L1 blockers are very good, approximately 70% of those patients show no response to the drug. A team of researchers from France hypothesized that gut microbiota imbalance may be one of the factors that cause nonresponse. To test this, mice with specific cancers, MCA-205 sarcoma and RET melanoma, were given PD-L1 blockers, and were then split into two groups. Because taking multiple antibiotics concurrently has been shown to cause imbalance in gut microbiota, one group of mice was given multiple antibiotics while the other received no antibiotics. The antibiotic group showed lower survival rates and a significant compromise in anti-tumor effects from PD-L1 blockers.

 

Next, differences in gut microbiota were investigated in a clinical setting, using quantitative metagenomics and shotgun sequencing on patient fecal samples. This revealed significant differences in the gut microbiota species composition between patients who showed response to PD-L1 blockers and those who showed no response. Notably, the presence of A. muciniphila in the gut microbiota was the strongest indicator of favorable clinical outcome. A. muciniphila was observed in about 70% of all patients who responded to PD-L1 blockers, 60% of all patients with no response but stable disease, and only 30% in all patients with continued disease progression.

 

In order to establish a cause-effect relationship between the dominance of species such as A. muciniphila and response to PD-L1 blockers, fecal microbiota transplantation using eight patient stool samples was performed on mice. Transplantation from four response patients into mice, but not from the other four non-response patients, resulted in tumor growth delay. This finding suggests that the human microbiome may play an important role in its interaction with the immune system, with future applications to the growing field of immunotherapy.

 

References

  1. What is the science of PD-1 and immunotherapy? Dana-Farber Cancer Institute. (2015).
  2. B. Routy, et al., Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors. Science 359, 91-97 (2018). doi: 10.1126/science.aan3706.
  3. Image retrieved from: https://en.wikipedia.org/wiki/Fecal_microbiota_transplant#/media/File:E_coli_at_10000x,_original.jpg
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