Dataset Information

Association of Fusobacterium nucleatum with Specific T-cell Subsets in the Colorectal Carcinoma Microenvironment.

ABSTRACT:

Purpose

While evidence indicates that Fusobacterium nucleatum (F. nucleatum) may promote colorectal carcinogenesis through its suppressive effect on T-cell-mediated antitumor immunity, the specific T-cell subsets involved remain uncertain.

Experimental design

We measured F. nucleatum DNA within tumor tissue by quantitative PCR on 933 cases (including 128 F. nucleatum-positive cases) among 4,465 incident colorectal carcinoma cases in two prospective cohorts. Multiplex immunofluorescence combined with digital image analysis and machine learning algorithms for CD3, CD4, CD8, CD45RO (PTPRC isoform), and FOXP3 measured various T-cell subsets. We leveraged data on Bifidobacterium, microsatellite instability (MSI), tumor whole-exome sequencing, and M1/M2-type tumor-associated macrophages [TAM; by CD68, CD86, IRF5, MAF, and MRC1 (CD206) multimarker assay]. Using the 4,465 cancer cases and inverse probability weighting method to control for selection bias due to tissue availability, multivariable-adjusted logistic regression analysis assessed the association between F. nucleatum and T-cell subsets.

Results

The amount of F. nucleatum was inversely associated with tumor stromal CD3⁺ lymphocytes [multivariable OR, 0.47; 95% confidence interval (CI), 0.28-0.79, for F. nucleatum-high vs. -negative category; P _trend = 0.0004] and specifically stromal CD3⁺CD4⁺CD45RO⁺ cells (corresponding multivariable OR, 0.52; 95% CI, 0.32-0.85; P _trend = 0.003). These relationships did not substantially differ by MSI status, neoantigen load, or exome-wide tumor mutational burden. F. nucleatum was not significantly associated with tumor intraepithelial T cells or with M1 or M2 TAMs.

Conclusions

The amount of tissue F. nucleatum is associated with lower density of stromal memory helper T cells. Our findings provide evidence for the interactive pathogenic roles of microbiota and specific immune cells.

SUBMITTER: Borowsky J

PROVIDER: S-EPMC8127352 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Association of <i>Fusobacterium nucleatum</i> with Specific T-cell Subsets in the Colorectal Carcinoma Microenvironment.

Borowsky Jennifer J Haruki Koichiro K Lau Mai Chan MC Dias Costa Andressa A Väyrynen Juha P JP Ugai Tomotaka T Arima Kota K da Silva Annacarolina A Felt Kristen D KD Zhao Melissa M Gurjao Carino C Twombly Tyler S TS Fujiyoshi Kenji K Väyrynen Sara A SA Hamada Tsuyoshi T Mima Kosuke K Bullman Susan S Harrison Tabitha A TA Phipps Amanda I AI Peters Ulrike U Ng Kimmie K Meyerhardt Jeffrey A JA Song Mingyang M Giovannucci Edward L EL Wu Kana K Zhang Xuehong X Freeman Gordon J GJ Huttenhower Curtis C Garrett Wendy S WS Chan Andrew T AT Leggett Barbara A BA Whitehall Vicki L J VLJ Walker Neal N Brown Ian I Bettington Mark M Nishihara Reiko R Fuchs Charles S CS Lennerz Jochen K JK Giannakis Marios M Nowak Jonathan A JA Ogino Shuji S

Clinical cancer research : an official journal of the American Association for Cancer Research 20210225 10

<h4>Purpose</h4>While evidence indicates that <i>Fusobacterium nucleatum</i> (<i>F. nucleatum</i>) may promote colorectal carcinogenesis through its suppressive effect on T-cell-mediated antitumor immunity, the specific T-cell subsets involved remain uncertain.<h4>Experimental design</h4>We measured <i>F. nucleatum</i> DNA within tumor tissue by quantitative PCR on 933 cases (including 128 <i>F. nucleatum</i>-positive cases) among 4,465 incident colorectal carcinoma cases in two prospective coho ...[more]

PMID: 33632927

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Project description:ImportanceEvidence indicates a complex link between gut microbiome, immunity, and intestinal tumorigenesis. To target the microbiota and immunity for colorectal cancer prevention and therapy, a better understanding of the relationship between microorganisms and immune cells in the tumor microenvironment is needed. Experimental evidence suggests that Fusobacterium nucleatum may promote colonic neoplasia development by downregulating antitumor T cell-mediated adaptive immunity.ObjectiveTo test the hypothesis that a greater amount of F nucleatum in colorectal carcinoma tissue is associated with a lower density of T cells in tumor tissue.Design, setting, and participantsA cross-sectional analysis was conducted on 598 rectal and colon carcinoma cases in 2 US nationwide prospective cohort studies with follow-up through 2006, the Nurses' Health Study (participants enrolled in 1976) and the Health Professionals Follow-up Study (participants enrolled in 1986). Tissue collection and processing were performed from 2002 through 2008, and immunity assessment, 2008 through 2009. From 2013 through 2014, the amount of F nucleatum in colorectal carcinoma tissue was measured by quantitative polymerase chain reaction assay; we equally dichotomized positive cases (high vs low). Multivariable ordinal logistic regression analysis was conducted in 2014 to assess associations of the amount of F nucleatum with densities (quartiles) of T cells in tumor tissue, controlling for clinical and tumor molecular features, including microsatellite instability, CpG island methylator phenotype, long interspersed nucleotide element-1 (LINE-1) methylation, and KRAS, BRAF, and PIK3CA mutation status. We adjusted the 2-sided α level to .013 for multiple hypothesis testing.Main outcomes and measuresDensities of CD3+, CD8+, CD45RO (protein tyrosine phosphatase receptor type C [PTPRC])+, and FOXP3+ T cells in tumor tissue, determined by means of tissue microarray immunohistochemical analysis and computer-assisted image analysis.ResultsF nucleatum was detected in colorectal carcinoma tissue in 76 (13%) of 598 cases. Compared with F nucleatum-negative cases, F nucleatum-high cases were inversely associated with the density of CD3+ T cells (for a unit increase in quartile categories of CD3+ T cells as an outcome: multivariable odds ratio, 0.47 [95% CI, 0.26-0.87]; P for trend = .006). The amount of F nucleatum was not significantly associated with the density of CD8+, CD45RO+, or FOXP3+ T cells (P fortrend = .24, .88, and .014, respectively).Conclusions and relevanceThe amount of tissue F nucleatum is inversely associated with CD3+ T-cell density in colorectal carcinoma tissue. On validation, our human population data may provide an impetus for further investigations on potential interactive roles of Fusobacterium and host immunity in colon carcinogenesis.

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