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. 2021 Jan;70(1):47-59.
doi: 10.1007/s00262-020-02657-x. Epub 2020 Jul 4.

Differential immune microenvironmental features of microsatellite-unstable colorectal cancers according to Fusobacterium nucleatum status

Affiliations

Differential immune microenvironmental features of microsatellite-unstable colorectal cancers according to Fusobacterium nucleatum status

Ji Ae Lee et al. Cancer Immunol Immunother. 2021 Jan.

Abstract

It has been suggested that Fusobacterium nucleatum (Fn) may differentially impact tumor immune responses according to microsatellite instability (MSI) status in colorectal cancers (CRCs). We aimed to reveal the detailed relationship between intratumoral Fn and immune microenvironmental features in MSI-high CRCs. A total of 126 MSI-high CRCs were subjected to analyses for intratumoral Fn DNA load using quantitative PCR and for densities of tumor-infiltrating immune cells, including CD3+ T cells, CD4+ T cells, CD8+ T cells, FoxP3+ T cells, CD68+ macrophages, CD163+ macrophages, and CD177+ neutrophils, at invasive margin (IM) and center of tumor (CT) areas using computational image analysis of immunohistochemistry. Based on the Fn load, the 126 MSI-high CRCs were classified into Fn-high, -low, and -negative subgroups. The Fn-high subset of MSI-high CRCs was significantly correlated with larger tumor size and advanced invasion depth (p = 0.017 and p = 0.034, respectively). Compared with the Fn-low/negative subgroup, Fn-high tumors demonstrated significantly lower density of FoxP3+ cells in both IM and CT areas (p = 0.002 and p = 0.003, respectively). Additionally, Fn-high was significantly associated with elevated CD163+ cell to CD68+ cell ratio in only CT areas of MSI-high CRCs (p = 0.028). In conclusion, the Fn-enriched subset of MSI-high CRCs is characterized by increased tumor growth and invasion and distinct immune microenvironmental features, including decreased FoxP3+ T cells throughout the tumor and increased proportion of M2-polarized macrophages in the tumor center. These findings collectively support that Fn may be linked to pro-tumoral immune responses in MSI-high CRCs.

Keywords: Colorectal carcinoma; Gut microbiome; Gut microbiota; Tumor immunity; Tumor immunology.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1
Comprehensive analysis of tumor-infiltrating immune cells and immune responses according to Fn status in MSI-high CRCs. a Comparisons of CD3+ T cell densities of IM (left) or CT (right) area between Fn-high and Fn-low/negative MSI-high CRCs. b Comparisons of CD8+ T cell densities of IM (left) or CT (right) area between Fn-high and Fn-low/negative MSI-high CRCs. c Comparisons of CD4+ T cell densities of IM (left) or CT (right) area between Fn-high and Fn-low/negative MSI-high CRCs. d Comparisons of FoxP3+ T cell densities of IM (left) or CT (right) area between Fn-high and Fn-low/negative MSI-high CRCs. e Comparisons of CD68+ macrophage densities of IM (left) or CT (right) area between Fn-high and Fn-low/negative MSI-high CRCs. f Comparisons of CD163+ macrophage densities of IM (left) or CT (right) area between Fn-high and Fn-low/negative MSI-high CRCs. g Comparisons of CD177+ neutrophil densities of IM (left) or CT (right) area between Fn-high and Fn-low/negative MSI-high CRCs. h A comparison of peritumoral TLS activity (maximum diameter of the largest TLS) between Fn-high and Fn-low/negative MSI-high CRCs. i A comparison of PD-L1 expression in immune cells (H-score of PD-L1 immunohistochemical staining in immune cells) between Fn-high and Fn-low/negative MSI-high CRCs. (j, k) Correlation scatter plots between Fn load and FoxP3+ T cell density of the IM (j) or CT (k) area in MSI-high CRCs
Fig. 2
Fig. 2
Differential immune cell density ratios according to Fn status in MSI-high CRCs. a Comparisons of FoxP3+ T cell density to CD4+ T cell density ratios of the IM (left) or CT (right) area between Fn-high and Fn-low/negative MSI-high CRCs. b Comparisons of CD163+ macrophage density to CD68+ macrophage density ratios of the IM (left) or CT (right) area between Fn-high and Fn-low/negative MSI-high CRCs
Fig. 3
Fig. 3
Characterization of the Fn-associated immune microenvironment in MSI-high CRC. a Representative photomicrographs of FoxP3, CD163, and CD68 IHC according to combined Fn (Fn-high and Fn-low/negative) and region (IM and CT) status. In contrast to Fn-low/negative tumors, there is scanty infiltration of FoxP3+ cells in both IM and CT areas of Fn-high tumors. Note the feature that most CD68+ cells are nearly overlap with CD163+ cells in the same CT area of an Fn-high tumor, indicating the high proportion of M2 macrophages among tumor-infiltrating macrophages. b A graphical summary of this study

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