The role of the gut microbiome in ICB-induced anti-tumor response and toxicity

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PROJECT SUMMARY Immune checkpoint blockade (ICB) has transformed clinical oncology by inducing durable responses and increasing survival rates in many types of cancers, including melanoma. However, only a subset of patients benefits, and it is unclear what determines a patient’s response to therapy. In addition, ICB can lead to immune- related adverse events (irAEs) that limit therapy and cause off-target tissue toxicities. Combination therapy with anti-cytotoxic T-lymphocyte associated protein 4 (-CTLA-4) and anti-programmed death ligand 1 (-PD-L1) exhibits the strongest efficacy, in terms of survival, compared with single agent treatments, yet this is associated with a greater irAE frequency. Recent studies have delineated roles for the gut microbiome in serving as a biomarker of ICB responsiveness, a potential therapeutic, and in some cases association with irAEs. With this proposal, we aim to increase understanding of the gut microbiome-immune system axis in combination ICB therapy. Recent work from our lab has highlighted roles for dendritic cells (DCs), professional antigen-presenting cells (APCs) of the immune system, in ICB response as well as ICB-associated irAEs. Moreover, we found that modulation of the gut microbiome via antibiotic treatment altered response to -CTLA-4: use of metronidazole prior to ICB resulted in ~90% tumor regression upon -CTLA-4 treatment without intestinal irAE. In addition, the efficacy of -CTLA-4 in metronidazole treatment conditions was associated with increases in type 1 conventional DC (cDC1) amounts and activation status, consistent with prior clinical studies implicating a role for cDC1s in favorable ICB response in melanoma patients. Thus, we hypothesize that specific microbes within the gut microbiome induce increased activity of cDC1s, which regulate favorable responses to ICB treatment and, upon dysregulation, contribute to ICB-mediated colitis. We propose to examine this hypothesis in two aims. In Aim 1, we will identify the role of APCs in linking the gut microbiome to ICB-mediated anti-tumor immunity. We will utilize fecal samples from melanoma patients to repopulate the gut microbiome of antibiotic- treated mice (fecal microbiome transplantation, FMT). We will evaluate microbiome composition, immune cell profiles, and intestinal inflammation (irAEs) in melanoma-bearing mice treated with combination ICB. In addition, mice with a deficiency of cDC1s will be used to examine roles for this subset of APCs in ICB response and toxicity following FMT with patient-derived material. In Aim 2, we seek to characterize the relationship between metronidazole and effect on the microbiome and ICB response. We will utilize FMT with patient-derived material from non-responders and metronidazole treatment to examine whether depletion of anaerobic bacteria via metronidazole is sufficient to convert a non-responder into a responder. We will further examine the microbiome composition and identify links to immune cell status and activity upon metronidazole treatment. Our studies will delineate whether specific microbes from human fecal samples correlate with key immune signatures or irAEs, thereby deepening understanding of mechanisms by which the gut microbiome regulates ICB responsiveness.