Abstract 5154: Bacterium LF-3: A dual player in colorectal cancer, shaping prognosis and immune responses

Abstract

Abstract Background: Colorectal cancer is distinctive for its heightened intra-tumor bacterial presence. While previous studies concentrated on the genus level, the impact of unclassified bacteria, identified through extensive genome sequencing, has been underexplored. Methods: Utilizing samples from colorectal cancer patients in the Cancer Microbiome Atlas project (TCMA), we applied phyloseq for a nuanced analysis of microbial abundance disparities between tumor and paracancer tissues. Prognostic implications of microbial enrichment were explored through survival analysis, with mechanistic insights gleaned from Gene Set Enrichment Analysis (GSEA). Results: We meticulously examined 151 colorectal cancer tumors and 22 corresponding para-cancer tissues, scrutinizing a total of 1217 microbial species. We observed that 240 species exhibited a statistically significant enrichment in tumor samples. A focused investigation involving 22 tumor and para-cancer tissue pairs unveiled 35 species with notable enrichment specifically within tumors. A subset of 25 species, including well-documented entities like Fusobacterium sp. oral taxon 370 and Streptococcus oralis, emerged consistently across both comprehensive and paired analyses. We then delved into the prognostic implications of these enriched bacteria. Strikingly, patients with bacterium LF-3 positivity exhibited significantly improved prognoses compared to those without (HR 0.40, 95% CI 0.18-0.91, log-rank p = 0.024). Considering the pivotal role of Microsatellite Instability (MSI) status in the context of Tumor Immuno-Microenvironment (TIME) and prognosis, our analysis of bacterium LF-3 encompassed both MSI-H and MSS CRC cases, with proportions of 12/28 (43%) and 55/102 (54%), respectively. Even after meticulous adjustments for MSI status, bacterium LF-3 maintained a robust correlation with prognosis (HR 0.42, 95% CI 0.18-0.99, p = 0.048), highlighting its independent prognostic significance. Further exploration among MSS patients (N = 112) unearthed intricate details about the impact of bacterium LF-3 on tumor signaling pathways. TNF-α and IFN-γ pathways were significantly up-regulated in bacterium LF-3-positive cases, while the MYC pathway, PI3K pathway, and various cell cycle-related pathways (G2M checkpoint, The E2 factor [E2F] targets, and mitotic spindle assembly) were down-regulated. As for TIME, bacterium LF-3 positivity correlated with the significant enrichment of CD4+ Th2 cells, suggesting a potential role in modulating immune responses. Conclusion: Bacterium LF-3 in colorectal cancer reveals a dual role, instigating inflammation and tumorigenesis, yet simultaneously activating the innate immune system and promoting cellular immunity. This dual functionality contributes to improved patient prognosis, highlighting the intricate interplay between microbes, immune responses, and colorectal cancer outcomes. Citation Format: Kunli Du, Feilong Zhao, Fan Feng. Bacterium LF-3: A dual player in colorectal cancer, shaping prognosis and immune responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5154.