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Fusobacterium nucleatum in Colorectal Cancer Relates to Immune Response Differentially by Tumor Microsatellite Instability Status.
Cancer Immunol Res. 2018 11; 6(11):1327-1336.CI

Abstract

The presence of Fusobacterium nucleatum (F. nucleatum) in colorectal carcinoma tissue has been associated with microsatellite instability (MSI), lower-level T-cell infiltrates, and poor clinical outcomes. Considering differences in the tumor-immune microenvironment between MSI-high and non-MSI-high carcinomas, we hypothesized that the association of F. nucleatum with immune response might differ by tumor MSI status. Using samples from 1,041 rectal and colon cancer patients within the Nurses' Health Study and Health Professionals Follow-up Study, we measured F. nucleatum DNA in tumor tissue by a quantitative polymerase chain reaction assay. Multivariable logistic regression models were used to examine the association between F. nucleatum status and histopathologic lymphocytic reactions or density of CD3+ cells, CD8+ cells, CD45RO (PTPRC)+ cells, or FOXP3+ cells in strata of tumor MSI status. We adjusted for potential confounders, including CpG island methylator phenotype; LINE-1 methylation; and KRAS, BRAF, and PIK3CA mutations. The association of F. nucleatum with tumor-infiltrating lymphocytes (TIL) and intratumoral periglandular reaction differed by tumor MSI status (P interaction = 0.002). The presence of F. nucleatum was negatively associated with TIL in MSI-high tumors [multivariable odds ratio (OR), 0.45; 95% confidence interval (CI), 0.22-0.92], but positively associated with TIL in non-MSI-high tumors (multivariable OR 1.91; 95% CI, 1.12-3.25). No significant differential association was observed for peritumoral lymphocytic reaction, Crohn-like lymphoid reaction, or T-cell densities. In conclusion, the association of F. nucleatum with immune response to colorectal carcinoma differs by tumor MSI status, suggesting that F. nucleatum and MSI status interact to affect antitumor immune reactions. Cancer Immunol Res; 6(11); 1327-36. ©2018 AACR See related Spotlight on p. 1290.

Authors+Show Affiliations

Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. Broad Institute of MIT and Harvard, Cambridge, Massachusetts.Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri.Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. Department of Epidemiology and Biostatistics, and the Ministry of Education Key Lab of Environment and Health, School of Public Health, Huazhong University of Science and Technology, Hubei, P.R. China.Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. Department of Medical Oncology, Chinese PLA General Hospital, Beijing, P.R. China.Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. College of Pharmacy, Zhejiang Chinese Medical University, Zhejiang, P.R. China.Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.Department of Gastroenterology, Rheumatology, and Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Japan.Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. Department of Food Science and Biotechnology, Dongguk University, Goyang, the Republic of Korea.Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.Broad Institute of MIT and Harvard, Cambridge, Massachusetts. Research Division, Joslin Diabetes Center, Boston, Massachusetts.Broad Institute of MIT and Harvard, Cambridge, Massachusetts. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. Broad Institute of MIT and Harvard, Cambridge, Massachusetts. Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. Broad Institute of MIT and Harvard, Cambridge, Massachusetts.Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts.Yale Cancer Center, New Haven, Connecticut. Department of Medicine, Yale School of Medicine, New Haven, Connecticut. Smilow Cancer Hospital, New Haven, Connecticut.Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. shuji_ogino@dfci.harvard.edu marios_giannakis@dfci.harvard.edu. Broad Institute of MIT and Harvard, Cambridge, Massachusetts. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. shuji_ogino@dfci.harvard.edu marios_giannakis@dfci.harvard.edu. Broad Institute of MIT and Harvard, Cambridge, Massachusetts. Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30228205

Citation

Hamada, Tsuyoshi, et al. "Fusobacterium Nucleatum in Colorectal Cancer Relates to Immune Response Differentially By Tumor Microsatellite Instability Status." Cancer Immunology Research, vol. 6, no. 11, 2018, pp. 1327-1336.
Hamada T, Zhang X, Mima K, et al. Fusobacterium nucleatum in Colorectal Cancer Relates to Immune Response Differentially by Tumor Microsatellite Instability Status. Cancer Immunol Res. 2018;6(11):1327-1336.
Hamada, T., Zhang, X., Mima, K., Bullman, S., Sukawa, Y., Nowak, J. A., Kosumi, K., Masugi, Y., Twombly, T. S., Cao, Y., Song, M., Liu, L., da Silva, A., Shi, Y., Gu, M., Li, W., Koh, H., Nosho, K., Inamura, K., ... Ogino, S. (2018). Fusobacterium nucleatum in Colorectal Cancer Relates to Immune Response Differentially by Tumor Microsatellite Instability Status. Cancer Immunology Research, 6(11), 1327-1336. https://doi.org/10.1158/2326-6066.CIR-18-0174
Hamada T, et al. Fusobacterium Nucleatum in Colorectal Cancer Relates to Immune Response Differentially By Tumor Microsatellite Instability Status. Cancer Immunol Res. 2018;6(11):1327-1336. PubMed PMID: 30228205.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Fusobacterium nucleatum in Colorectal Cancer Relates to Immune Response Differentially by Tumor Microsatellite Instability Status. AU - Hamada,Tsuyoshi, AU - Zhang,Xuehong, AU - Mima,Kosuke, AU - Bullman,Susan, AU - Sukawa,Yasutaka, AU - Nowak,Jonathan A, AU - Kosumi,Keisuke, AU - Masugi,Yohei, AU - Twombly,Tyler S, AU - Cao,Yin, AU - Song,Mingyang, AU - Liu,Li, AU - da Silva,Annacarolina, AU - Shi,Yan, AU - Gu,Mancang, AU - Li,Wanwan, AU - Koh,Hideo, AU - Nosho,Katsuhiko, AU - Inamura,Kentaro, AU - Keum,NaNa, AU - Wu,Kana, AU - Meyerhardt,Jeffrey A, AU - Kostic,Aleksandar D, AU - Huttenhower,Curtis, AU - Garrett,Wendy S, AU - Meyerson,Matthew, AU - Giovannucci,Edward L, AU - Chan,Andrew T, AU - Fuchs,Charles S, AU - Nishihara,Reiko, AU - Giannakis,Marios, AU - Ogino,Shuji, Y1 - 2018/09/18/ PY - 2018/03/19/received PY - 2018/07/03/revised PY - 2018/09/11/accepted PY - 2018/9/20/pubmed PY - 2019/10/23/medline PY - 2018/9/20/entrez SP - 1327 EP - 1336 JF - Cancer immunology research JO - Cancer Immunol Res VL - 6 IS - 11 N2 - The presence of Fusobacterium nucleatum (F. nucleatum) in colorectal carcinoma tissue has been associated with microsatellite instability (MSI), lower-level T-cell infiltrates, and poor clinical outcomes. Considering differences in the tumor-immune microenvironment between MSI-high and non-MSI-high carcinomas, we hypothesized that the association of F. nucleatum with immune response might differ by tumor MSI status. Using samples from 1,041 rectal and colon cancer patients within the Nurses' Health Study and Health Professionals Follow-up Study, we measured F. nucleatum DNA in tumor tissue by a quantitative polymerase chain reaction assay. Multivariable logistic regression models were used to examine the association between F. nucleatum status and histopathologic lymphocytic reactions or density of CD3+ cells, CD8+ cells, CD45RO (PTPRC)+ cells, or FOXP3+ cells in strata of tumor MSI status. We adjusted for potential confounders, including CpG island methylator phenotype; LINE-1 methylation; and KRAS, BRAF, and PIK3CA mutations. The association of F. nucleatum with tumor-infiltrating lymphocytes (TIL) and intratumoral periglandular reaction differed by tumor MSI status (P interaction = 0.002). The presence of F. nucleatum was negatively associated with TIL in MSI-high tumors [multivariable odds ratio (OR), 0.45; 95% confidence interval (CI), 0.22-0.92], but positively associated with TIL in non-MSI-high tumors (multivariable OR 1.91; 95% CI, 1.12-3.25). No significant differential association was observed for peritumoral lymphocytic reaction, Crohn-like lymphoid reaction, or T-cell densities. In conclusion, the association of F. nucleatum with immune response to colorectal carcinoma differs by tumor MSI status, suggesting that F. nucleatum and MSI status interact to affect antitumor immune reactions. Cancer Immunol Res; 6(11); 1327-36. ©2018 AACR See related Spotlight on p. 1290. SN - 2326-6074 UR - https://www.unboundmedicine.com/medline/citation/30228205/Fusobacterium_nucleatum_in_Colorectal_Cancer_Relates_to_Immune_Response_Differentially_by_Tumor_Microsatellite_Instability_Status_ L2 - http://cancerimmunolres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=30228205 DB - PRIME DP - Unbound Medicine ER -