Link Between Microbiome and Anti-tumor Immunity Established

Immune checkpoint inhibitors have been a major breakthrough in cancer immunotherapy, however they don't work for everybody and are often associated with significant side effects. Efforts to understand the regulation of anti-tumor immunity point to the importance of the gut microbiome, but the underlying molecular mechanism(s) remain largely elusive.

Now, a worldwide collaboration 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. The team has identified a cocktail of 11 bacterial strains that activated the immune system and slowed the growth of melanoma in mice. A study, published today in Nature Communications, 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.

"Immunotherapies have extended the lives of many cancer patients. However, the incredible effects we are seeing today are only the tip of the iceberg. By studying mechanisms of treatment response versus resistance, we can eventually expand the number of people who benefit from immunotherapy," says Thomas Gajewski, M.D., Ph.D., from the University of Chicago Medicine. "This study provides an important step toward this goal. 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."

"Our study establishes a formal link between the microbiome and anti-tumor immunity and points to the role of the UPR in this process, answering a long-sought question for the field," elaborates Ze’ev Ronai, Ph.D., senior author of the study. "These results also identify a collection of bacterial strains that could turn on anti-tumor immunity and biomarkers that could be used to stratify people with melanoma for treatment with select checkpoint inhibitors."