Towards modulating the gut microbiota to enhance the efficacy of immune-checkpoint inhibitors.

The gut microbiota modulates immune processes both locally and systemically. This includes whether and how the immune system reacts to emerging tumours, whether antitumour immune responses are reactivated during treatment with immune-checkpoint inhibitors (ICIs), and whether unintended destructive immune pathologies accompany such treatment. Advances over the past decade have established that the gut microbiota is a promising target and that modulation of the microbiota might overcome resistance to ICIs and/or improve the safety of treatment. However, the specific mechanisms through which the microbiota modulates antitumour immunity remain unclear. Understanding the biology underpinning microbial associations with clinical outcomes in patients receiving ICIs, as well as the landscape of a 'healthy' microbiota would provide a critical foundation to facilitate opportunities to effectively manipulate the microbiota and thus improve patient outcomes. In this Review, we explore the role of diet and the gut microbiota in shaping immune responses during treatment with ICIs and highlight the key challenges in attempting to leverage the gut microbiome as a practical tool for the clinical management of patients with cancer.

Diet-driven microbial ecology underpins associations between cancer immunotherapy outcomes and the gut microbiome.

The gut microbiota shapes the response to immune checkpoint inhibitors (ICIs) in cancer, however dietary and geographic influences have not been well-studied in prospective trials. To address this, we prospectively profiled baseline gut (fecal) microbiota signatures and dietary patterns of 103 trial patients from Australia and the Netherlands treated with neoadjuvant ICIs for high risk resectable metastatic melanoma and performed an integrated analysis with data from 115 patients with melanoma treated with ICIs in the United States. We observed geographically distinct microbial signatures of response and immune-related adverse events (irAEs). Overall, response rates were higher in Ruminococcaceae-dominated microbiomes than in Bacteroidaceae-dominated microbiomes. Poor response was associated with lower fiber and omega 3 fatty acid consumption and elevated levels of C-reactive protein in the peripheral circulation at baseline. Together, these data provide insight into the relevance of native gut microbiota signatures, dietary intake and systemic inflammation in shaping the response to and toxicity from ICIs, prompting the need for further studies in this area.

Targeting the Microbiome to Overcome Resistance.

Immune checkpoint inhibition has revolutionized the treatment of many cancers, including melanoma. However, primary and acquired resistance remain key challenges for the field. Promising results from a phase I clinical trial recently published in Science highlight the potential of modulating the microbiome via fecal transplant to overcome resistance to immunotherapy.