Abstract 6520: Intratumoral microbiome profiling using high-depth whole-genome sequencing highlighted Cutibacterium acnes in chemoresistance in ovarian cancer

Abstract Background: High-grade serous ovarian cancer (HGSC) is the most lethal gynecologic malignancy, with high recurrence rates and the development of chemoresistance significantly limiting patient survival. While the tumor microenvironment (TME), including extracellular matrix (ECM) remodeling and epithelial-mesenchymal transition (EMT), is known to contribute to chemoresistance, non-genetic factors remain poorly understood. Emerging evidence implicates the intratumoral microbiome in modulating the TME and influencing chemoresistance in several solid tumors, but how composition and diversity of the bacterial communities contribute to the efficacy of neoadjuvant chemotherapy (NACT) in HGSC is not known. Methods: We analyzed multi-omics data from HGSC samples previously reported. Tumor-associated microbial communities were profiled using metagenomic analysis of whole-genome sequencing data and ECM- and EMT-associated gene expression profiles were evaluated through RNA sequencing. Samples included tumor tissues from 30 patients with complete gross resection (CGR) at primary surgery, neoadjuvant chemotherapy (NACT) excellent responders (NACT-ER), and poor responders (NACT-PR). Each group had 10 patients with a primary tumor site and two synchronous metastatic sites. Results: Microbial profiling revealed that Cutibacterium acnes (CB) is the most common and abundant organism within HGSC intratumoral microbiome. It was more abundant in tumor and metastatic tissue from patients treated with NACT (P=0.001) versus those who had upfront CGR. Integration of RNA sequencing data demonstrated a strong correlation between CB abundance and EMT signature, which emerged as the most significantly enriched hallmark gene set according to the Gene Set Enrichment Analysis. Additionally, tumors enriched in CB exhibited transcriptional signatures associated with aggressive tumor behavior (e.g., enhanced activity of TNFA signaling, adipogenesis, and oxidative phosphorylation). Tumors with high CB abundance displayed a distinct ECM organization, decreased infiltration of T and B cells and increased abundance of fibroblasts, neutrophils, and endothelial cells, potentially indicative of an angiogenic phonotype. Conclusions: The tumor-associated microbiome, particularly CB, may play a critical role in HGSC chemoresistance through EMT induction and ECM remodeling. This study highlights the potential of microbiome in shaping tumor phenotypes and identifies possible therapeutic targets. Citation Format: Tatiana V. Karpinets, Xiaogan Wu, Wayne W. Xy, Amma Asare, Sara Corvigno, Joseph Celestino, Ridge T. Rogers, Raymond N. Montoya, Mark S. Kim, Pamela T. Soliman, Shannon N. Westin, P. Andrew Futreal, Amir A. Jazaeri, Anil K. Sood, Jianhua Zhang, Sanghoon Lee. Intratumoral microbiome profiling using high-depth whole-genome sequencing highlighted Cutibacterium acnes in chemoresistance in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6520.