Uncovering longitudinal microbiome changes in ICI resistance and toxicity

In the last decade, rapid advances have been made in melanoma treatment, most notably the introduction of immune checkpoint inhibitors (ICIs), which stimulate the body’s immune system to kill melanoma cells. However, many patients do not respond to ICIs (termed ICI resistance), and others develop autoimmune-like side effects (termed immune-related adverse events, or irAEs). Discovery of easily-measurable markers that identify melanoma patients who may not respond to ICIs or that may be developing irAEs will help clinicians maximize the benefit from ICIs and minimize side effects.

The gut microbiome (GMB) is a community of bacteria that resides in the body’s intestines that can influence how effective the body’s cancer-fighting immune cells are against melanoma and how well they respond to stimulation by ICIs. The GMB can also produce small molecules, or “metabolites”, that can similarly influence the behavior of the immune system against melanoma. The makeup of the GMB and its metabolites can change while patients are receiving ICIs, but it is not known whether these changes correlate with development of ICI resistance or irAEs. Thus, further study of how the GMB evolves while on ICI therapy may enable use of the GMB or its byproducts as clinical markers of ICI resistance and irAEs, allowing for rapid intervention for patients that may not be responding to ICIs or developing potentially dangerous side effects.

In this study, we propose to compare GMB evolution patterns in melanoma patients that respond to ICIs in different ways to learn more about whether GMB evolution patterns could eventually be used to predict ICI resistance or irAEs. We also propose to compare levels of short-chain fatty acids (SCFAs), which are GMB metabolites that can shape ICI response, in patients with different types of ICI resistance and in patients with vs without irAEs. This will allow us to assess the potential of using SCFA levels to predict ICI resistance or irAEs.