University of Oulu

Borowsky, J., Haruki, K., Lau, M., Dias Costa, A., Väyrynen, J., Ugai, T., Arima, K., da Silva, A., Felt, K., Zhao, M., Gurjao, C., Twombly, T., Fujiyoshi, K., Väyrynen, S., Hamada, T., Mima, K., Bullman, S., Harrison, T., Phipps, A., Peters, U., Ng, K., Meyerhardt, J., Song, M., Giovannucci, E., Wu, K., Zhang, X., Freeman, G., Huttenhower, C., Garrett, W., Chan, A., Leggett, B., Whitehall, V., Walker, N., Brown, I., Bettington, M., Nishihara, R., Fuchs, C., Lennerz, J., Giannakis, M., Nowak, J., Ogino, S. (2021) Association of Fusobacterium nucleatum with Specific T-cell Subsets in the Colorectal Carcinoma Microenvironment.Clinical Cancer Research, OnlineFirst. https://doi.org/10.1158/1078-0432.CCR-20-4009

Association of Fusobacterium nucleatum with specific T-cell subsets in the colorectal carcinoma microenvironment

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Author: Borowsky, Jennifer1,2,3,4; Haruki, Koichiro1,5; Lau, Mai Chan1,5;
Organizations: 1Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
2Department of Pathology, Center for Integrated Diagnostics, Massachusetts General Hospital and Harvard Medical School, Boston, MA
3Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
4School of Medicine, The University of Queensland, Brisbane, Queensland, Australia
5Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
6Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
7Cancer and Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital, and University of Oulu, Oulu, Finland
8Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA
9Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA
10Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA
11Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA
12Department of Epidemiology, University of Washington, Seattle, WA
13Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA
14Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA
15Division of Gastroenterology, Massachusetts General Hospital, Boston, MA
16Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
17Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA
18Broad Institute of MIT and Harvard, Cambridge, MA
19Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA
20The Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia
21Conjoint Internal Medicine Laboratory, Pathology Queensland, Queensland Health, Brisbane, Queensland, Australia
22Envoi Specialist Pathologists, Brisbane, Queensland, Australia
23Yale Cancer Center, New Haven, CT
24Department of Medicine, Yale School of Medicine, New Haven, CT
25Smilow Cancer Hospital, New Haven, CT
26Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
27Cancer Immunology and Cancer Epidemiology Programs, Dana-Farber Harvard Cancer Center, Boston, MA
Format: article
Version: accepted version
Access: embargoed
Persistent link: http://urn.fi/urn:nbn:fi-fe2021042611954
Language: English
Published: American Association for Cancer Research, 2021
Publish Date: 2022-03-26
Description:

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; Ptrend = 0.0004] and specifically stromal CD3⁺CD4⁺CD45RO⁺ cells (corresponding multivariable OR, 0.52; 95% CI, 0.32–0.85; Ptrend = 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.

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Series: Clinical cancer research
ISSN: 1078-0432
ISSN-E: 1557-3265
ISSN-L: 1078-0432
Volume: OnlineFirst
DOI: 10.1158/1078-0432.CCR-20-4009
OADOI: https://oadoi.org/10.1158/1078-0432.CCR-20-4009
Type of Publication: A1 Journal article – refereed
Field of Science: 3122 Cancers
Subjects:
Funding: We would like to thank the participants and staff of the Nurses’ Health Study and the Health Professionals Follow-up Study for their valuable contributions, as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL,GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK,OR, PA, RI, SC, TN, TX, VA, WA, and WY. This work was supported by NIH grants (P01 CA87969 to M.J. Stampfer; UM1 CA186107 to M.J. Stampfer; P01 CA55075 to W.C. Willett; UM1 CA167552 to W.C. Willett; U01 CA167552 to W.C. Willett and L.A. Mucci; P50 CA127003 to C.S. Fuchs; R01 CA118553 to C.S. Fuchs; R01CA169141 to C.S. Fuchs; R01 CA137178 to A.T. Chan; K24 DK098311 to A.T.Chan; R35 CA197735 to S. Ogino; R01 CA151993 to S. Ogino; K07 CA190673 to R.Nishihara; K07 CA188126 to X. Zhang; R37 CA225655 to J.K. Lennerz; R01CA248857 to S. Ogino, U. Peters, and A.I. Phipps; and P50 CA101942 to G.J.Freeman), Cancer Research UK’s Grand Challenge Award (UK C10674/A27140 to K. Ng, W.S. Garrett, M. Giannakis, C. Huttenhower, and S. Ogino), Nodal Award (2016-02) from the Dana-Farber Harvard Cancer Center (to S. Ogino and G.J.Freeman), a Stand Up to Cancer Colorectal Cancer Dream Team Translational Research grant (SU2C-AACR-DT22-17 to C.S. Fuchs and M. Giannakis), and grants from the Project P Fund, The Friends of the Dana-Farber Cancer Institute, Bennett Family Fund, and the Entertainment Industry Foundation through National Colorectal Cancer Research Alliance and SU2C. Stand Up to Cancer is a division of the Entertainment Industry Foundation. The indicated SU2C research grant is administered by the American Association for Cancer Research, the scientific partner ofSU2C. J. Borowsky was supported by a grant from the Australia Awards-Endeavour Scholarships and Fellowships Program. K. Haruki was supported by fellowship grants from the Uehara Memorial Foundation and the Mitsukoshi Health and Welfare Foundation. K. Arima was supported by a grant from Overseas Research Fellowship (JP2018-60083) from Japan Society for the Promotion of Science. K. Fujiyoshi was supported by a fellowship grant from the Uehara Memorial Foundation. S.A.Väyrynen was supported by Finnish Cultural Foundation and Orion Research Foundation. J.A. Meyerhardt research was supported by the Douglas Gray Woodruff Chair fund, the Guo Shu Shi Fund, Anonymous Family Fund for Innovations in Colorectal Cancer, P fund, and the George Stone Family Foundation. M. Giannakis was supported by an ASCO Conquer Cancer Foundation Career Development Award. A.T. Chan is a Stuart and Suzanne Steele MGH Research Scholar.
Copyright information: © 2021 American Association for Cancer Research.