Author ORCID Identifier
0000-0001-8601-9949
Date of Graduation
5-2024
Document Type
Dissertation (PhD)
Program Affiliation
Microbiology and Infectious Diseases
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Robert Jenq, MD
Committee Member
James Allison, PhD
Committee Member
Michael Curran, PhD
Committee Member
Gretchen Diehl, PhD
Committee Member
Anna Konovalova, PhD
Committee Member
Anne Marie Krachler, PhD
Abstract
Immune checkpoint inhibitors (ICIs) have been revolutionary in the fight against cancer by recruiting the host immune system as an agent for attack on malignant cells. Unfortunately, immune-related adverse events (irAEs), including ICI-mediated colitis (IMC), are common side effects that result from immune cell mediated damage on healthy tissues. Recent studies have highlighted a role for the gut microbiota in modulating ICI-mediated anti-tumor responses, but less is known regarding how the gut microbiota may impact on irAEs. Considering that the gastrointestinal tract harbors thousands of unique microbial species, many of which are known to modulate the immune system, microbes and microbe-derived factors are likely important modulators of IMC risk and severity.
In two related studies, we used clinical samples to first profile the gut microbial composition to better understand which taxa are associated with IMC. The first study is a case series of IMC patients (n=12) that received fecal microbiota transplant (FMT) as a salvage therapy for treatment of refractory IMC. A majority of patients (83%) achieved symptom improvement after one FMT treatment, while 92% achieved IMC clinical remission by the end of the study following repeat FMT. We found that patients with a composition more dissimilar to donors at baseline were more likely to respond favorably to FMT. Symptom resolution and complete response to FMT was marked by significant increases in alpha diversity as well as increases in taxa including Bifidobacterium and Collinsella. Additional insights from the study include a decrease in CD8+ T cells in complete responders. In a separate study, fecal samples were prospectively collected from IMC patients at onset of toxicity presentation (n=31). An examination of the microbiota composition of these samples revealed two major subsets of IMC patients, including a larger one with a more dysbiotic gut microbiota at baseline, characterized by loss of obligately anaerobic species and expansion of potential pathobionts such as Streptococcus and Escherichia. Patients from this subset went on to have poor clinical outcomes post-IMC onset, including reduced overall survival and a higher incidence of infectious complications. A metabolomic evaluation demonstrated that short chain fatty acids (SCFAs), including acetate, propionate and butyrate, were significantly depleted in this group of IMC patients. In a murine model of IMC, we found that a brief, five-day administration of an antibiotic cocktail led to loss of obligately anaerobic species and expansion of aerotolerant taxa like Enterococcus, Lactobacillus, and Escherichia, similar to the subset of patients with poor clinical outcomes. Interestingly, examining these mice demonstrated increased bacterial translocation to mesenteric lymph nodes, indicating that intestinal microbial dysbiosis in this setting led to an impairment in intestinal barrier function. Gained knowledge through patient profiling and pre-clinical mouse models will better our understanding of factors related to IMC and subsequent related poor outcomes for patients in the future.
Keywords
gut microbiome, immune checkpoint inhibitors, microbiology, clinical research
Included in
Bacteria Commons, Medical Immunology Commons, Medical Microbiology Commons, Translational Medical Research Commons