Checkpoint Checkmate: Microbiota Modulation of Cancer Immunotherapy

In recent years, immune checkpoint inhibitors (ICIs)5, which block the ability of cancer cells to evade killing by CD8+ T cells, have begun to revolutionize cancer treatment. Since 2011, 6 different ICIs targeting T-cell (PD-1 or CTLA-4) or tumor (PD-L1) surface proteins have been approved for the treatment of several cancers, including non-small cell lung cancer and metastatic melanoma, with dozens of additional clinical trials ongoing. However, despite impressive clinical outcomes in some patients, the efficacy of ICI therapy remains highly variable, and the key drivers of this heterogeneity are not fully understood. Three recent articles (1–3) provide intriguing and compelling evidence that patients' gut microbiotas, or the communities of microbes that inhabit their gastrointestinal tracts, affect their responsiveness to ICIs. Here, we highlight key elements of these studies and discuss outstanding questions and future directions. The mammalian gut is home to a complex microbial ecosystem that continuously interacts with and regulates its host's immune system. Early in life, the developing gut microbiota helps train and shape the immature immune system, and improper immune responses later in life (e.g., Crohn disease and allergies) are often associated with an altered gut microbiota. Similarly, germ-free and antibiotic-treated animals are functionally deficient in both innate and adaptive immunity. Although the human gut microbiota is consistently dominated by 2 phyla, Firmicutes and Bacteroidetes, no microbial strains are universally conserved among all individuals. Thus, interpersonal variation within the gut microbiota is 1 plausible explanation for the range of clinical outcomes observed during ICI therapy. This putative connection between the microbiota and immunotherapy was greatly strengthened in 2015 with the observation that specific gut bacteria can influence ICI efficacy in preclinical mouse models of cancer. These 2015 studies did not encompass data from patient cohorts, but in 2018, 3 articles by …