Gut microbiome directs immune system to fight cancer.
It is known that immunotherapies, which release the brakes of the body’s immune system to launch an efficient tumour attack, are a major breakthrough in cancer therapy. However, these treatments don’t work for everybody and are often associated with significant side effects. By studying mechanisms of treatment response versus resistance, researchers hope to expand the number of people who benefit from immunotherapy. Now, a study from researchers at Sanford Burnham Prebys demonstrates a causal link between the gut microbiome and the immune system’s ability to fight cancer. The team state their results also identify a collection of bacterial strains that could turn on anti-tumor immunity and biomarkers that could be used to stratify people with melanoma for treatment with cancer immunotherapy. The opensource study is published in the journal Nature Communications.
Previous studies show a growing collection of research supports the role of the gut microbiome in effective immunotherapy. Studies have shown that antibiotics and select probiotics reduce the effectiveness of treatment, while certain bacterial strains can improve the effectiveness of the treatment. However, the underlying molecular mechanisms remain largely elusive. The current study genetically modifies mice to alter their intestinal microbiota flora to demonstrate limited tumour expansion and immunity.
The current study utilises a genetic mouse model which lacks the gene for RING finger protein 5 (RNF5), which helps remove inappropriately folded or damaged proteins. Results show the RNF5-lacking mice were able to inhibit the growth of melanoma tumours, provided they had an intact immune system and gut microbiome, via several immune system components, including Toll-like receptors and select dendritic cells, within the gut intestinal environment. Data findings show the reduced unfolded protein response (UPR), a cellular signaling pathway which maintains protein health, is also associated with the altered gut microbiomes seen in the mice.
The lab state bioinformatics allowed them to identify 11 bacterial strains that were enriched in the guts of the RNF5-lacking mice. They go on to add that transferring these bacterial strains to regular mice that lack intestinal bacteria induced anti-tumour immune response and slowed tumour growth. To confirm that the results were relevant in human disease, the group obtained tissue samples from three cohorts of people with metastatic melanoma who subsequently received a cancer immunotherapy.
The team surmise their study establishes a formal link between the microbiome and anti-tumour immunity, and points to the role of the UPR in this process. For the future, the researchers plan to determine which metabolites the bacteria are producing which slow tumour growth, which could then be used to enhance anti-tumour immunity and define possible prebiotics to enrich their presence in the gut of melanoma patients.
Source: Sanford Burnham Prebys