Widely hailed as a breakthrough in cancer therapy, immunotherapies release the brakes of the body’s immune system to launch an efficient tumor attack, however, these treatments don’t work for every person 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 states their results also identify a collection of bacterial strains with the potential to turn on anti-tumor immunity and act as biomarkers to identify people with melanoma most likely to benefit from 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. Antibiotics and select probiotics are well-established in muting the effectiveness of treatment, while certain bacterial strains were shown to 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 tumor expansion and immunity.
The current study utilizes a genetic mouse model lacking 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 tumors, 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 maintaining protein health, is also associated with the altered gut microbiomes seen in the mice.
The lab states bioinformatics allowed them to identify 11 bacterial strains enriched in the guts of the RNF5-lacking mice. They go on to add transferring these bacterial strains to regular mice lacking intestinal bacteria-induced anti-tumor immune response and slowed tumor growth. To confirm 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 surmises their study establishes a formal link between the microbiome and anti-tumor 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 tumor growth, which could then be used to enhance anti-tumor immunity and define possible prebiotics to enrich their presence in the gut of melanoma patients.
Source: Sanford Burnham Prebys
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