Gut microbiome plays key role in fighting cancer

There is a causal link between the gut microbiome and the immune system's ability to fight cancer, according to a new study led by researchers at Sanford Burnham Prebys Medical Discovery Institute in San Diego, California, which was published in the journal Nature Communications.

Researchers identified 11 bacterial strains that activated the immune system and slowed the growth of melanoma in mice, according to the study abstract. In addition, researchers said the results point to the role of unfolded protein response (UPR), a cellular signaling pathway that maintains protein health (homeostasis). Reduced UPR was seen in melanoma patients who are responsive to immune checkpoint therapy, revealing potential markers for patient stratification.

Although immune checkpoint therapies have significantly improved patient survival rates, metastatic melanoma remains the deadliest form of skin cancer, according to the American Cancer Society. Even when used as part of combination therapy, immune checkpoint inhibitors only benefit about half of patients, and these responses may involve autoimmune-related side effects, limited durability, and, at times, resistance to therapy.

Accumulating evidence supports the role of the gut microbiome in effective immune therapy, researchers say. Antibiotics and select probiotics reduce treatment efficacy, while certain bacterial strains enhance efficacy.

As part of the study, the research team are studied a genetic mouse model that lacks the gene for RING finger protein 5 (RNF5), a ubiquitin ligase that helps remove inappropriately folded or damaged proteins. While these molecular traits are critical for the current study, the mice don't show any outward signs of disease, researchers say.

However, the RNF5-lacking mice were able to inhibit the growth of melanoma tumors, provided they had an intact immune system and gut microbiome. Treating these mice with a cocktail of antibiotics or housing the mice with their regular littermates abolished the anti-tumor immunity phenotype and consequently, tumor rejection, indicating the important role of the gut microbiome in anti-tumor immunity, the study said.

Mapping the immune components engaged in the process revealed several immune system components, including Toll-like receptors and select dendritic cells, within the gut intestinal environment. Reduced UPR was commonly identified in immune and intestinal epithelial cells and was sufficient for immune cell activation. Reduced UPR signaling was also associated with the altered gut microbiomes seen in the mice.

Advanced bioinformatics techniques allowed the scientists to identify 11 bacterial strains that were enriched in the guts of the RNF5-lacking mice. Transferring these 11 bacterial strains to regular mice that lack intestinal bacteria (germ-free) induced anti-tumor immune response and slowed tumor growth.

To confirm that the results were relevant in human disease, the scientists obtained tissue samples from three cohorts of people with metastatic melanoma who subsequently received checkpoint inhibitor treatment. Researchers said reduced expression of UPR components correlated with responsiveness to treatment, suggesting that there are potentially predictive biomarkers for the selection of patients who should receive immune checkpoint therapy.

The next step, scientists say, is to determine what the bacteria are producing that slows tumor growth. These products, called metabolites, could then be tested to determine their ability to enhance anti-tumor immunity but also to define possible prebiotics that may be used to enrich their presence in the gut of melanoma patients.