The intestinal microbiome directs the immune system against cancer

The advent of immune inhibitors at checkpoints, which "release the brakes" of the immune system to trigger an effective tumor attack, is a major advance in the field of cancer immunotherapy. However, these treatments do not work for everyone and are often associated with significant side effects. The possibility of stratifying patients according to the potential response to immune checkpoint inhibitors may therefore be a factor in the treatment of cancer. Efforts to understand the regulation of anti-tumor immunity (when the immune system fights a tumor) underscore the importance of the intestinal microbiome. However, the underlying molecular mechanism (s) remain largely elusive.

At present, a global collaboration involving more than 40 scientists and three hospitals, led by researchers at Sanford Burnham Prebys, 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 highlights the role of the non-folded protein response (UPR), a cell signaling pathway that maintains protein health (homeostasis). A reduction in UPR has been observed in patients with melanoma responsive to immune treatment at checkpoints, thus revealing potential markers for stratification of the patient. The study was published in Nature Communications.

"Immunotherapies have prolonged the lives of many cancer patients. However, the incredible effects we see today are just the tip of the iceberg. By studying the mechanisms of response to treatment versus resistance, we may eventually increase the number of people benefiting from immunotherapy, "says Thomas Gajewski, MD, Ph.D., a professor at the AbbVie Foundation of Immunotherapy in Canada. at the University of Chicago Medicine. "This study is an important step in achieving this goal. Researchers have identified 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 effectiveness of control point blocking immunotherapy, this additional mechanistic analysis should help select patients who will respond to the treatment and to guide the new therapeutic development. "

Although immune point-of-care therapies have dramatically improved patient survival rates, metastatic melanoma remains the most lethal form of skin cancer, according to the American Cancer Society. Even when they are used in combination, immune checkpoint inhibitors only benefit about half of patients. These responses may involve autoimmune side effects, limited durability (the length of time a patient responds to treatment), and sometimes resistance to resistance. therapy. The accumulated evidence confirms the role of the gut microbiome in effective immune therapy: antibiotics and some probiotics reduce the effectiveness of treatment, while some bacterial strains improve the effectiveness. This study sheds new light on these observations.

"Our study establishes a formal link between the microbiome and anti-tumor immunity and highlights the role of the UPR in this process, responding to a long-sought issue in the field," says Ze & # 39; ev Ronai, Ph.D., senior author of the study and professor at the Cancer Center, designated by the NCI of Sanford Burnham Prebys. "These results also identify a set of bacterial strains that can activate anti-tumor immunity and biomarkers that can be used to stratify people with melanoma for treatment with certain inhibitors." checkpoint. "

"Boring" mice give interesting results

Ronai has devoted much of his lab's efforts to understanding how cancer responds to stress and becomes resistant to treatment. As part of his work, he and his team are studying a genetic mouse model that lacks the finger protein RING 5 (RNF5), a ubiquitin ligase that helps eliminate misfolded or damaged proteins. Although these molecular characteristics are essential for the present study, mice show no outward sign of disease.

"We call them" boring mice "because they have no noticeable phenotype," Ronai said.

However, mice lacking RNF5 were able to inhibit the growth of melanoma tumors, provided they had an intact immune system and an intestinal microbiome. Treating these mice with an antibiotic cocktail or housing mice with their litter mates (wild-type) abolished the anti-tumor immunity phenotype and, therefore, tumor rejection, indicating the role important of the intestinal microbiome in the anti-tumor immunity. The mapping of the immune components involved in the process revealed several components of the immune system, including Toll-like receptors and selected dendritic cells, in the intestinal intestinal environment. Reduced UPR was commonly identified in immune and intestinal epithelial cells and was sufficient for the activation of immune cells. Reduced UPR signaling was also associated with altered intestinal microbiomes observed in mice.

Advanced bioinformatics techniques allowed scientists to identify 11 enriched bacterial strains in the intestines of mice lacking RNF5. The transfer of these 11 bacterial strains to regular mice devoid of intestinal bacteria (without germs) induces an anti-tumor immune response and a slowing of tumor growth.

To confirm that the results were relevant to the human disease, the scientists obtained tissue samples from three cohorts of people with metastatic melanoma who were subsequently treated with a checkpoint inhibitor. Indeed, reduced expression of UPR components (sXBP1, ATF4, and BiP) correlated with responsiveness to treatment, suggesting the existence of biomarkers potentially predictive for the selection of patients to receive control treatment immune.

Scientists then plan to determine what the bacterium produces to slow tumor growth. These products, called metabolites, could then be tested to determine their ability to enhance anti-tumor immunity, but also to identify potential prebiotics that can be used to enhance their presence in the intestines of melanoma patients. .

"We believe this research applies to another fundamental question about the balance between anti-tumor immunity and autoimmunity," Ronai said. "Since mice lacking RNF5 are also prone to intestinal inflammation – a side effect observed for some immune-control therapies – we can harness this powerful model to study how we can tilt the balance between the immune system and the immune system. # 39; autoimmunity and anti-tumor immunity people benefit from these remarkable therapies. "