IBCN 2023: Exploring the Impact of Microbiome in the Response of Combined Radiation with Immune Checkpoint Blockade in Muscle Invasive Bladder Cancer

(UroToday.com) Radiation therapy (RT) is a promising bladder-sparing option for muscle invasive bladder cancer (MIBC) treatment, yet 30% of patients do not respond and half later die of metastasis. Improved antitumor responses when RT is combined with PD-1/ PD-L1 blockade (CT) have been described in mice, yet determinants of CT success remain flagrantly misunderstood.

As such, gut microbiome composition influences PD-1 blockade efficacy and its modification potentiates combined RT and PD-L1 blockade activity. To add, responding patients with favorable gut microbiomes have enhanced antitumor immunity. They thus aimed to document the role of patients’ microbiome in polarizing anti-tumor immune responses to CT and predicting CT success in MIBC.

Fecal material from a responder (R) and non-responder (NR) MIBC patient was gavaged into 20 germ-free mice. 3 weeks after the last gavage, MB49 cells were delivered subcutaneously. Once tumors reached 0.1-0.15cm3, mice were randomized into 4 groups control; anti-PD-L1; RT; RT+anti-PD-L1. 7 days later, tumors were dissociated and stools collected for single-cell immune and 16S sequencing. Correlation networks were built (TransNet, Microbiome R packages) and visualized in Cytoscape.

We show feasibility and robust engraftment of human FMT to germ-free mice in an MIBC tumor model. FMT from NR lessened the known beneficial effects of RT in the MB49 model compared to FMT from R. Transkingdom analysis of immune and microbe data shows robust statistical interactions between immunosuppression and enrichment in microbes associated with poor outcomes in humans.

To our knowledge, this is the first study to use FMT as a modulator of response in the context of radiation therapy combinations in MIBC. These findings could be used to select patients who will benefit most from a personalized therapeutic approach.

Presented by: Éva Michaud, Urologic Oncology Research Division, McGill University Health Centre, Montreal, Canada.

Written by: Stephen B. Williams, MD, MBA, MS @SWilliams_MD on Twitter during the International Bladder Cancer Network (IBCN) Annual Meeting, September 29-30, 2023, Montreal, Canada