title: Fusobacterium nucleatum and T Cells in Colorectal Carcinoma.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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
  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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Mima
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Sukawa
authors.affiliation: Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts3Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.
authors.forename: Reiko
authors.initials: R
authors.lastname: Nishihara
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Zhi Rong
authors.initials: ZR
authors.lastname: Qian
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Mai
authors.initials: M
authors.lastname: Yamauchi
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts4Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Inamura
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Sun A
authors.initials: SA
authors.lastname: Kim
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Masuda
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Nowak
authors.affiliation: Department of Gastroenterology, Rheumatology, and Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Nosho
authors.affiliation: Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, Massachusetts8Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
authors.forename: Aleksandar D
authors.initials: AD
authors.lastname: Kostic
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts8Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
authors.forename: Marios
authors.initials: M
authors.lastname: Giannakis
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts8Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
authors.forename: Hideo
authors.initials: H
authors.lastname: Watanabe
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts8Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
authors.forename: Susan
authors.initials: S
authors.lastname: Bullman
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts9Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.
authors.forename: Danny A
authors.initials: DA
authors.lastname: Milner
authors.affiliation: Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Curtis C
authors.initials: CC
authors.lastname: Harris
authors.affiliation: Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts3Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.
authors.forename: Edward
authors.initials: E
authors.lastname: Giovannucci
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts8Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
authors.forename: Levi A
authors.initials: LA
authors.lastname: Garraway
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts10Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts10Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Glenn
authors.initials: G
authors.lastname: Dranoff
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts12Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Chan
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts8Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
authors.forename: Wendy S
authors.initials: WS
authors.lastname: Garrett
authors.affiliation: Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, Massachusetts8Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
authors.forename: Curtis
authors.initials: C
authors.lastname: Huttenhower
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts11Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Charles S
authors.initials: CS
authors.lastname: Fuchs
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts3Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts5Department of Pathology, Brigham and Women's Hospital.
authors.forename: Shuji
authors.initials: S
authors.lastname: Ogino
mesh_terms: D056704:Adaptive Immunity; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D002277:Carcinoma / Q000235:genetics / Q000276:immunology* / Q000382:microbiology* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics / Q000276:immunology* / Q000382:microbiology* / Q000473:pathology; D003430:Cross-Sectional Studies; D019175:DNA Methylation; D004269:DNA, Bacterial / Q000235:genetics; D005260:Female; D016967:Fusobacterium nucleatum / Q000235:genetics / Q000276:immunology*; D054884:Host-Pathogen Interactions; D006801:Humans; D007150:Immunohistochemistry; D016015:Logistic Models; D018655:Lymphocyte Count; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D016017:Odds Ratio; D060888:Real-Time Polymerase Chain Reaction; D021521:Ribotyping; D012307:Risk Factors; D013601:T-Lymphocytes / Q000276:immunology*; D046888:Tissue Array Analysis; D059016:Tumor Microenvironment; D014481:United States
chemical_list: D014408:Biomarkers, Tumor; D004269:DNA, Bacterial