The advent of immune checkpoint inhibitors--which "release the brakes" of the body's immune system to launch an efficient tumor attack--are a major breakthrough in cancer immunotherapy. However, these treatments don't work for everybody and are often associated with significant side effects. The ability to stratify patients based on potential response to immune checkpoint inhibitors could therefore personalize cancer treatment. Efforts to understand the regulation of anti-tumor immunity (when the immune system fights a tumor) point to the importance of the gut microbiome. However, the underlying molecular mechanism(s) remain largely elusive.
Now, a worldwide collaboration involving more than 40 scientists and three hospitals has demonstrated a causal link between the gut microbiome and the immune system's ability to fight cancer. Together, the researchers identified a cocktail of 11 bacterial strains that activated the immune system and slowed the growth of melanoma in mice. The study also points 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. The study was published in Nature Communications.
The investigators have pinpointed the UPR as an important link between the gut microbiota and anti-tumor immunity. Given previous work indicating a causal role for the host microbiota in the efficacy of checkpoint blockade immunotherapy, this additional mechanistic insight should help select patients who will respond to treatment and also help to guide new therapeutic development."
The team was 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.
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 (wildtype) littermates abolished the anti-tumor immunity phenotype and consequently, tumor rejection--indicating the important role of the gut microbiome in anti-tumor 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 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. 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 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.
"We believe this research applies to another fundamental question pertaining to the balance between anti-tumor immunity and autoimmunity," says the author. "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 anti-tumor immunity, which could help more people benefit from these remarkable therapies."
Gut microbiome directs the immune system to fight cancer
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