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Original Investigation
August 2015

Fusobacterium nucleatum and T Cells in Colorectal Carcinoma

Author Affiliations
  • 1Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
  • 2Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
  • 3Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
  • 4Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
  • 5Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 6Department of Gastroenterology, Rheumatology, and Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Japan
  • 7Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
  • 8Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts
  • 9Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
  • 10Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 11Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 12Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts
JAMA Oncol. 2015;1(5):653-661. doi:10.1001/jamaoncol.2015.1377
Abstract

Importance  Evidence 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.

Objective  To 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 Participants  A 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 Measures  Densities 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.

Results  F 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 Relevance  The 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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