|Title||Association of Fusobacterium nucleatum with Specific T-cell Subsets in the Colorectal Carcinoma Microenvironment.|
|Publication Type||Journal Article|
|Year of Publication||2021|
|Authors||Borowsky J, Haruki K, Lau MChan, Costa ADias, Väyrynen JP, Ugai T, Arima K, da Silva A, Felt KD, Zhao M, Gurjao C, Twombly TS, Fujiyoshi K, Väyrynen SA, Hamada T, Mima K, Bullman S, Harrison TA, Phipps AI, Peters U, Ng K, Meyerhardt JA, Song M, Giovannucci EL, Wu K, Zhang X, Freeman GJ, Huttenhower C, Garrett WS, Chan AT, Leggett BA, Whitehall VLJ, Walker N, Brown I, Bettington M, Nishihara R, Fuchs CS, Lennerz JK, Giannakis M, Nowak JA, Ogino S|
|Journal||Clin Cancer Res|
|Date Published||2021 May 15|
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.
|Alternate Journal||Clin Cancer Res|
|PubMed Central ID||PMC8127352|
|Grant List||R35 CA197735 / CA / NCI NIH HHS / United States |
R01 CA118553 / CA / NCI NIH HHS / United States
P01 CA087969 / CA / NCI NIH HHS / United States
R01 CA248857 / CA / NCI NIH HHS / United States
P50 CA101942 / CA / NCI NIH HHS / United States
R37 CA225655 / CA / NCI NIH HHS / United States
U01 CA167552 / CA / NCI NIH HHS / United States
R01 CA137178 / CA / NCI NIH HHS / United States
K24 DK098311 / DK / NIDDK NIH HHS / United States
UM1 CA186107 / CA / NCI NIH HHS / United States
R01 CA169141 / CA / NCI NIH HHS / United States
P50 CA127003 / CA / NCI NIH HHS / United States
K07 CA190673 / CA / NCI NIH HHS / United States
P01 CA055075 / CA / NCI NIH HHS / United States
R01 CA151993 / CA / NCI NIH HHS / United States
K07 CA188126 / CA / NCI NIH HHS / United States
UM1 CA167552 / CA / NCI NIH HHS / United States
Annacarolina Da Silva, M.D.