Role of the intestinal microbiome and microbial-derived metabolites in immune checkpoint blockade immunotherapy of cancer

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that block immune inhibitory pathways. Administration of ICIs augments T cell-mediated immune responses against tumor, resulting in improved overall survival in cancer patients. It has emerged that the intestinal microbiome can modulate responses to ICIs via the host immune system and that the use of antibiotics can lead to reduced efficacy of ICIs. Recently, reports that fecal microbiota transplantation can lead to ICI therapy responses in patients previously refractory to therapy suggest that targeting the microbiome may be a viable strategy to reprogram the tumor microenvironment and augment ICI therapy. Intestinal microbial metabolites may also be linked to response rates to ICIs. In addition to response rates, certain toxicities that can arise during ICI therapy have also been found to be associated with the intestinal microbiome, including in particular colitis. A key mechanistic question is how certain microbes can enhance anti-tumor responses or, alternatively, predispose to ICI-associated colitis. Evidence has emerged that the intestinal microbiome can modulate outcomes to ICI therapies via two major mechanisms, including those that are antigen-specific and those that are antigen-independent. Antigen-specific mechanisms occur when epitopes are shared between microbial and tumor antigens that could enhance, or, alternatively, reduce anti-tumor immune responses via cross-reactive adaptive immune cells. Antigen-independent mechanisms include modulation of responses to ICIs by engaging innate and/or adaptive immune cells. To establish microbiome-based biomarkers of outcomes and specifically modulate the intestinal microbiome to enhance efficacy of ICIs in cancer immunotherapy, further prospective interventional studies will be required.