Intratumoural bacteria promote myeloid inflammation and disease progression in clear cell Renal Cell Carcinoma: TRACERx Renal

Authors list

Alice Martin Anne-Laure Cattin Parise Lockwood Martha A Zepeda-Rivera Clara Becker Taja Barber Irene Lobon Krupa Thakkar Leo J Bickley Zayd Tippu Laura Marandino Marija Miletić Lucy Meader Mary Green Donald Bell Brian Hanley Barbara Ibrazo Yus Fiona Byrne Charlotte Spencer Scott Shepherd Annika Fendler Lewis Au Daqi Deng Angel Fernández Sanromán Sarah Rudman

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Abstract

Intratumoural bacteria are increasingly recognised as active contributors to disease progression in solid tumours. In this study, we characterised bacteria across 616 whole-genome sequenced samples from 143 clear cell Renal Cell Carcinoma tumours within the TRACERx Renal cohort. Using in situ imaging and bacterial culture, we confirmed bacterial colonisation and identified the commensal Cutibacterium, as the predominant bacterium. Cutibacterium enrichment associated with larger (p=0.019), more advanced (p=0.024) tumours and shorter Progression Free Survival (PFS) (p=0.0022) in our cohort and the independent TCGA cohort (n=511; Stage: p=0.0011; PFS: p=4.4×10⁻4). Integrating bulk RNA-seq, in situ imaging, and spatial transcriptomics revealed Cutibacterium colonisation associating with neutrophil recruitment and myeloid inflammation. In vitro, Cutibacterium induced sustained expression of neutrophil-attracting chemokines in macrophages, supporting its active role in shaping the tumour microenvironment. Together, our findings establish intratumoural bacteria as novel modulators of ccRCC progression and highlight their potential as therapeutic targets.