Speaker: Stephan Spahn
Host: Heike Brötz-Oesterhelt (CMFI)
Date & Time: 14.12.2023 | 12:30 – 2 p.m.
Venue: Lecture hall 3M07, GUZ
Public event. No registration needed.
Immunotherapy with immune-checkpoint blockade (ICB) has revolutionized cancer therapy and is the only chance of cure for patients with advanced disease. As only a minority of patients respond, an urgent need exists to understand and overcome ICB resistance. Tumors are colonized by a metabolically active tumor microbiome. However, whereas multiple studies have highlighted a central role of the gut microbiota in ICB response, the interplay between the tumor microbiome, tumor immunity, and ICB response remains elusive.
We thus interrogated the tumor microbiome of 292 patients before treatment with ICB to identify bacterial species and bacterial functions that are associated with the response to ICB. In addition, RNAseq and immunohistochemistry was performed for the majority of the tumor samples to study the impact of tumor-resident bacteria on key human host immunopopulations and transcriptomics.
The analysis using an optimized 5R 16S-sequencing pipeline – allowing classification of low biomass bacteria- revealed multiple intratumoral bacterial taxa associated with outcomes to ICB treatment. Moreover, using PICRUSt2 to predict the metagenome functions of the tumor-resident bacteria, we identified several bacterial metabolic pathways that are significantly associated with resistance to ICB therapy and an immunosuppressed tumormicroenviroment. In a next step, we explored and validated the impact of these bacteria derived metabolites using in vitro and in vivo experiments.
To sum up, this study establishes the tumor microbiome as a novel prognostic determinant and therapeutic target of ICB-response. Metabolites derived from intratumor bacteria can directly affect the tumor immune microenvironment and, subsequently, the response to therapy.