How does the gut microbiome help fight cancer?
A worldwide collaboration, led by Sanford Burnham Prebys Medical Discovery Institute in the US, has demonstrated a causal link between the gut microbiome and the immune system’s ability to fight cancer.
The advent of immune checkpoint inhibitors — which ‘release the brakes’ of the body’s immune system to launch an efficient tumour attack — was a major breakthrough in cancer immunotherapy. But 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 (the length of time a patient responds to treatment) and, at times, resistance to therapy.
Accumulating evidence supports the role of the gut microbiome in effective immune therapy: antibiotics and select probiotics reduce treatment efficacy, while certain bacterial strains enhance efficacy. Now, scientists have confirmed that there is indeed a link between the gut microbiome and the immune system’s ability to fight cancer.
Writing in the journal Nature Communications, the researchers described a cocktail of 11 bacterial strains that activated the immune system and slowed the growth of melanoma in mice. They also outlined the role of unfolded protein response (UPR), a cellular signalling 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 and thus more personalised cancer treatment.
“Our study establishes a formal link between the microbiome and antitumour immunity and points to the role of the UPR in this process, answering a long-sought question for the field,” said Ze’ev Ronai, senior author on the study. “These results also identify a collection of bacterial strains that could turn on antitumour immunity and biomarkers that could be used to stratify people with melanoma for treatment with select checkpoint inhibitors.”
Ronai has dedicated much of his lab’s efforts to understanding how cancer responds to stress and becomes treatment resistant. As part of this work, he and his team are studying 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.
“We call them the ‘boring mice’ because they don’t have a notable phenotype,” Ronai said.
However, the RNF5-lacking mice were able to inhibit the growth of melanoma tumours, 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 (wildtype) littermates abolished the antitumour immunity phenotype and consequently, tumour rejection — indicating the important role of the gut microbiome in antitumour immunity.
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 signalling 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 antitumour immune response and slowed tumour 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. Indeed, reduced expression of UPR components (sXBP1, ATF4 and BiP) correlated with responsiveness to treatment, suggesting that there are potentially predictive biomarkers for the selection of patients who should receive immune checkpoint therapy.
Next, the scientists plan to determine what the bacteria are producing that slows tumour growth. These products, called metabolites, could then be tested to determine their ability to enhance antitumour immunity but also to define possible prebiotics that may be used to enrich their presence in the gut of melanoma patients.
“We believe this research applies to another fundamental question pertaining to the balance between antitumour immunity and autoimmunity,” Ronai said. “Because mice that lack RNF5 are also prone to developing gut inflammation — a side effect seen for certain immune checkpoint therapies — we can exploit this powerful model to study how we may tilt the balance between autoimmunity and antitumour immunity, which could help more people benefit from these remarkable therapies.”
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