Abstract 3597: Tumor bacteria, tumor-infiltrating T cells, and colorectal cancer survival outcomes
Authors: Tomotaka Ugai, Jennifer Borowsky, Yuxue Zhong, Satoko Ugai, Mai Chan Lau, Kota Arima, Koichiro Haruki, Marios Giannakis, Jonathan Nowak, Shuji Ogino
Journal: Cancer Research (2025)

Abstract Background: Colorectal cancer (CRC) is a heterogeneous tumor with complex interactions between tumor cells, immune cells, and microbiota in the tumor microenvironment. We hypothesized that T cell infiltrates might differ by colorectal tumor tissue bacteria. We also hypothesized that the presence of T-cell-associated tumor bacteria might be associated with worse clinical outcomes. Methods: We used a prospective cohort tumor biobank database of 831 incidence CRC cases with available tissue data in the Nurses’ Health Study and the Health Professionals Follow-up Study. To identify the tumor microbiota, we developed 16S rRNA gene sequencing and validated the data using quantitative PCR assays. We assessed tumor-infiltrating T-cell subsets using multiplexed immunofluorescence assays with digital image analyses and machine-learning algorithms. Spearman correlation test was performed to examine the correlation between the abundance of tumor microbiota and CD3+CD4+ or CD3+CD8+ T-cell densities. Multivariable Cox proportional hazards regression model was used to calculate hazard ratios (HRs) and 95% CIs for CRC-specific mortality. P values &amp;lt;0.005 were considered statistically significant. Results: Strong negative correlations were observed between CD3+CD4+ T-cell density and the abundance of Bacteroides fragilis (rho=-0.12, P&amp;lt;0.001), Fusobacterium canifelinum (rho=-0.11, P=0.001), Fusobacterium nucleatum (rho=-0.10, P=0.003), and Moryella indoligenes (rho=-0.08, P=0.007). We observed similar strong negative correlations between CD3+CD8+ T-cell density and Bordetella trematum (rho=-0.10, P=0.004), and Prevotella salivae (rho=-0.075, P=0.023). We further evaluated whether T-cell-associated bacteria were associated with poor prognosis. Among identified CD3+CD4+ T cell-associated bacteria, the presence of Moryella indoligenes [HR (95% CI), 2.82 (1.40-5.66); P=0.004], Campylobacter gracilis [HR (95% CI), 2.10 (1.22-3.61); P=0.008], and Fusobacterium nucleatum [HR (95% CI), 1.56 (1.17-2.30); P=0.004] were associated with higher CRC-specific mortality. We did not observe significant associations of CD3+CD8+T-cell-associated bacteria with poor prognosis. Conclusions: We identified immune-suppressive bacteria that were correlated with lower CD3+CD4+ and CD3+CD8+T cell densities in the tumor microenvironment. Among these immune-suppressive bacteria, Fusobacterium nucleatum, Moryella indoligenes, and Campylobacter gracilis were associated with both lower CD3+CD4+T cell density and worse survival. Our findings indicate that certain tumor microbiota, such as Fusobacterium nucleatum, suppresses anti-tumor T cell response, leading to the development and progression of CRC. By contrast, other tumor bacteria, such as Bacteroides fragilis, may suppress anti-tumor T cell response and have a key role in tumor initiation, but may not strongly affect clinical outcomes. Citation Format: Tomotaka Ugai, Jennifer Borowsky, Yuxue Zhong, Satoko Ugai, Mai Chan Lau, Kota Arima, Koichiro Haruki, Marios Giannakis, Jonathan Nowak, Shuji Ogino. Tumor bacteria, tumor-infiltrating T cells, and colorectal cancer survival outcomes [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 3597.