Microbiome influencers of checkpoint blockade-associated toxicity

Abstract

Immunotherapy has greatly improved cancer outcomes, yet variability in response and off-target tissue damage can occur with these treatments, including immune checkpoint inhibitors (ICIs). Multiple lines of evidence indicate the host microbiome influences ICI response and risk of immune-related adverse events (irAEs). As the microbiome is modifiable, these advances indicate the potential to manipulate microbiome components to increase ICI success. We discuss microbiome features associated with ICI response, with focus on bacterial taxa and potential immune mechanisms involved in irAEs, and the overall goal of driving novel approaches to manipulate the microbiome to improve ICI efficacy while avoiding irAE risk.

Figure 1.

Fecal microbiome associations with ICI response. (A) Fecal microbiomes linked with response to ICI show greater diversity, which is predicted to provide an appropriate balance between protective and inflammatory species in the gut (left). Favorable microbiomes associate with increased DC and T cell activation in the intestinal lamina propria (LP), lymph nodes (LN), and tumor (not shown), suggesting they promote effective T cell priming and activation in LNs that enables or enhances ICI response (right). (B) Non-favorable microbiomes show less diversity, which is predicted to promote a pro-inflammatory state and reduce protective factors in the gut (left). Non-favorable microbiomes associate with elevated LPS signatures, greater activation of myeloid responses, and increases in circulating neutrophil:lymphocyte ratios (NLR), suggesting microbiome-driven effects on the myeloid compartment interferes with ICI efficacy (right).

Figure 2.

Model of microbiome-mediated effects on ICI colitis. Microbiomes associated with increased risk of ICI colitis are predicted to elicit elevated production and/or immune recognition of MAMPs, resulting in increased pro-inflammatory cytokine production from intestinal immune subsets. These microbiomes are also expected to associate with reduced production of gut-protective factors such as SCFAs. These responses lead to induction of a pro-inflammatory state in the gut (left). Upon T cell activation by ICI and consequent production of T cell–produced inflammatory cytokines (e.g., IFN-γ, TNF-α), the intestinal environment is shifted further toward a pro-inflammatory state that drives epithelial barrier disruption, increases exposure to MAMPs, and further promotes localized inflammatory responses that further tissue damage, which drive clinical signs of ICI colitis.