Fusobacterium nucleatum in Colorectal Cancer Relates to Immune Response Differentially by Tumor Microsatellite Instability Status

摘要

The presence of Fusobacterium nucleatum in colorectal carcinoma tissue has been associated with microsatellite instability (MSI), lower-level T-cell infiltrates, and poor clinical outcomes. Considering differences in the tumor-immune microenvironment of carcinomas with high or low MSI, we hypothesized that the association of F. nucleatum with immune response might differ by tumor MSI status. Using samples from 1,041 rectal and colon cancer patients within the Nurses’ Health Study and Health Professionals Follow-up Study, we measured F. nucleatum DNA in tumor tissue by a quantitative polymerase chain reaction assay. Multivariable logistic regression models were used to examine the association between F. nucleatum status and histopathologic lymphocytic reactions or density of CD3⁺ cells, CD8⁺ cells, CD45RO (PTPRC)⁺ cells, or FOXP3⁺ cells in strata of tumor MSI status. We adjusted for potential confounders including CpG island methylator phenotype, LINE-1 methylation, and KRAS, BRAF, and PIK3CA mutations. The association of F. nucleatum with tumor-infiltrating lymphocytes (TIL) and intratumoral periglandular reaction differed by tumor MSI status (Pinteraction = 0.002). The presence of F. nucleatum was negatively associated with TIL in MSI-high tumors (multivariable odds ratio, 0.45; 95% confidence interval, 0.22–0.92), but positively associated with TIL in non-MSI-high tumors (multivariable odds ratio, 1.91; 95% confidence interval, 1.12–3.25). No significant differential association was observed for peritumoral lymphocytic reaction, Crohn’s-like lymphoid reaction, or T-cell densities. In conclusion, the association of F. nucleatum with immune response to colorectal carcinoma differs by tumor MSI status, suggesting that F. nucleatum and MSI status interact to affect anti-tumor immune reactions.