Association of Fusobacterium nucleatum with Specific T-cell Subsets in the Colorectal Carcinoma Microenvironment
Year: 2021
Type: article
Study design: Observational Study
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.
Source: Clinical Cancer Research
Authors: Jennifer Borowsky, Koichiro Haruki, Mai Chan Lau, Andressa Dias Costa, Juha P. Väyrynen, Tomotaka Ugai, Kota Arima, Annacarolina da Silva, Kristen D. Felt, Melissa Zhao, Carino Gurjao, Tyler S. Twombly, Kenji Fujiyoshi, Sara A. Väyrynen, Tsuyoshi Hamada, Kosuke Mima, Susan Bullman, Tabitha A. Harrison, Amanda I. Phipps, Ulrike Peters, Kimmie Ng, Jeffrey A. Meyerhardt, Mingyang Song, Edward L. Giovannucci, Kana Wu, Xuehong Zhang, Gordon J. Freeman, Curtis Huttenhower, Wendy S. Garrett, Andrew T. Chan, Barbara A. Leggett, Vicki L.J. Whitehall, Neal Walker, Ian Brown, Mark Bettington, Reiko Nishihara, Charles S. Fuchs, Jochen K. Lennerz, Marios Giannakis, Jonathan A. Nowak, Shuji Ogino
Institutions: Harvard University, The University of Queensland, QIMR Berghofer Medical Research Institute, Massachusetts General Hospital, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Dana-Farber/Harvard Cancer Center, Oulu University Hospital, University of Oulu, Fred Hutch Cancer Center, University of Washington, Broad Institute, Royal Brisbane and Women's Hospital, Queensland Health, Envoi Specialist Pathologists, Yale Cancer Center, Yale University, Smilow Cancer Hospital
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Dana Farber/ Harvard Cancer Center SPORE in Gastrointestinal Cancer, Calcium and Colorectal Cancer: Gene-Environment Interactions and Molecular Pathways, G11871972, Development of new treatments of non-viral hepatocellular carcinoma through targeting microbiota, G1791405362, Epigenetic Events and Colorectal Cancer Epidemiology, Dietary And Lifestyle Determinants Of Colon Cancer Recurrence and Survival, Inflammation and Colorectal Neoplasia, Accelerating Transdisciplinary Epidemiology of Colorectal Cancer, G3205903500, Dietary and Hormonal Determinants of Cancer in Women, Impact of Celecoxib and Inflammation on Survival in Stage III Colon Cancer, DF/HCC Kidney Cancer SPORE, Mentored Patient-Oriented Research in Digestive Diseases, Microbiome and chemoresistance in pancreatic cancer, Prospective Studies of Diet and Cancer in Men and Women, Long Term Multidisciplinary Study of Cancer in Women: The Nurses Health Study, Illuminating the evolutionary history of colorectal cancer metastasis: basic principles and clinical applications, Cancer Epidemiology Cohort in Male Health Professionals, Lifestyle, genetics and colonoscopy for colorectal cancer prevention, Leveraging Novel Randomized Clinical Trials of Vitamin D Supplementation in Patients with Colorectal Cancer: Impact on Survival and Anti-Tumor Immunity, Interdisciplinary Epidemiologic Consortium to Investigate T-cell Response in Colorectal Cancer, Precision Prevention Research Program, Cancer Epidemiology Cohort in Male Health Professionals
OpenAlex ID: W3131522853