Abstract 6518: Sex-biased intratumoral microbiome impact cancer cell proliferation and treatment outcomes in gastrointestinal cancers

Abstract Objectives: Sex differences in cancer treatment responses and disease prognosis are well-documented. Our study investigates the intratumoral microbiome, hypothesizing that its composition varies between sexes which contributes to the observed differences. Specifically, our study aims to identify sex-biased intratumoral microbiome and investigate their influence on host gene expression, survival rates, and responses to treatment. Method: We analyzed intratumoral microbiome abundance in 5 gastrointestinal cancers to identify differentially abundant (DA) microbes between sexes. After initial identification, these microbes were validated using independent datasets. A total of six large-scale intratumoral microbiome datasets were included for discovery and validation. We then assessed differential gene expression and gene set enrichment that are associated with these DA microbes. Experimental examination were carried out for two DA microbiome, Epstein-Barr virus (EBV) and Capnocytophaga, to assess their impact on cancer cell proliferation and responses to standard-of-care (SOC) treatments. Results: From more than one thousand microbes analyzed, we identified 22 DA microbiome, comprising 17 bacteria, 3 fungi, and 2 viruses, each validated with an independent dataset. EBV is one of the 22 reproducible DA microbiome found to be significantly male-enriched in gastric cancer (GC). Further analysis unveiled the association between intratumoral EBV infection and better overall survival in GC patients. To investigate whether the survival difference partially attributes to difference in response to treatments, we treated EBV positive and negative GC cell lines with 5 SOC chemotherapies. We observed that EBV infection sensitized 3 of 5 SOC treatments (paclitaxel, docetaxel, and 5-FU), while had no effects on the others (cisplatin, oxaliplatin). Moreover, pathway analysis revealed enrichment of inflammatory response, interferon response, and apoptosis pathways in EBV-infected GC. Capnocytophaga, a reproducible female-enriched microbiome in head and neck cancer (HNSC), was found to be significantly associated with improved survival. Further co-culturing experiments found that Capnocytophaga supernatant significantly inhibited HNSC cell proliferation in vitro. Conclusion: Our research identified intratumoral microbiome with sex-specific abundance patterns in gastrointestinal cancers. The identified DA microbes are closely associated with differences in the host transcriptome, drug responses, and survival outcomes. This underscores the potential of the intratumoral microbiome as a significant factor in personalized cancer treatment and management. Citation Format: Yuting Shan, Yingbo Huang, Adam Lee, Radwa Elmorsi, Tuyen Phan, R. Stephanie Huang. Sex-biased intratumoral microbiome impact cancer cell proliferation and treatment outcomes in gastrointestinal cancers [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 6518.