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Fusobacterium nucleatum and T cells in colorectal carcinoma
Kosuke Mima, Yasutaka Sukawa, Reiko Nishihara, Zhi Rong Qian, Mai Yamauchi, Kentaro Inamura, Sun A. Kim, Atsuhiro Masuda, Jonathan A. Nowak, Katsuhiko Nosho, Aleksandar D. Kostic, Marios Giannakis, Hideo Watanabe, Susan Bullman, Danny A. Milner, Curtis C. Harris, Edward Giovannucci, Levi A. Garraway, Gordon J. Freeman, Glenn Dranoff
Andrew T. Chan, Wendy S. Garrett, Curtis Huttenhower, Charles S. Fuchs, Shuji Ogino
Importance: 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. Design, Setting, and Participants: A cross-sectional analysiswas 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. Main Outcomes and Measures: 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 for trend = .24, .88, and .014, respectively). Conclusions and Relevance: 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.
https://doi.org/10.1001/jamaoncol.2015.1377
Published - 2015 Aug
10.1001/jamaoncol.2015.1377
Dive into the research topics of 'Fusobacterium nucleatum and T cells in colorectal carcinoma'. Together they form a unique fingerprint.
Fusobacterium nucleatum Medicine & Life Sciences 100%
Immunity Medicine & Life Sciences 25%
Long Interspersed Nucleotide Elements Medicine & Life Sciences 12%
Mima, K., Sukawa, Y., Nishihara, R., Qian, Z. R., Yamauchi, M., Inamura, K., Kim, S. A., Masuda, A., Nowak, J. A., Nosho, K., Kostic, A. D., Giannakis, M., Watanabe, H., Bullman, S., Milner, D. A., Harris, C. C., Giovannucci, E., Garraway, L. A., Freeman, G. J., ... Ogino, S. (2015). Fusobacterium nucleatum and T cells in colorectal carcinoma. JAMA Oncology, 1(5), 653-661. https://doi.org/10.1001/jamaoncol.2015.1377
Fusobacterium nucleatum and T cells in colorectal carcinoma. / Mima, Kosuke; Sukawa, Yasutaka; Nishihara, Reiko; Qian, Zhi Rong; Yamauchi, Mai; Inamura, Kentaro; Kim, Sun A.; Masuda, Atsuhiro; Nowak, Jonathan A.; Nosho, Katsuhiko; Kostic, Aleksandar D.; Giannakis, Marios; Watanabe, Hideo; Bullman, Susan; Milner, Danny A.; Harris, Curtis C.; Giovannucci, Edward; Garraway, Levi A.; Freeman, Gordon J.; Dranoff, Glenn; Chan, Andrew T.; Garrett, Wendy S.; Huttenhower, Curtis; Fuchs, Charles S.; Ogino, Shuji.
In: JAMA Oncology, Vol. 1, No. 5, 08.2015, p. 653-661.
Mima, K, Sukawa, Y, Nishihara, R, Qian, ZR, Yamauchi, M, Inamura, K, Kim, SA, Masuda, A, Nowak, JA, Nosho, K, Kostic, AD, Giannakis, M, Watanabe, H, Bullman, S, Milner, DA, Harris, CC, Giovannucci, E, Garraway, LA, Freeman, GJ, Dranoff, G, Chan, AT, Garrett, WS, Huttenhower, C, Fuchs, CS & Ogino, S 2015, 'Fusobacterium nucleatum and T cells in colorectal carcinoma', JAMA Oncology, vol. 1, no. 5, pp. 653-661. https://doi.org/10.1001/jamaoncol.2015.1377
Mima K, Sukawa Y, Nishihara R, Qian ZR, Yamauchi M, Inamura K et al. Fusobacterium nucleatum and T cells in colorectal carcinoma. JAMA Oncology. 2015 Aug;1(5):653-661. https://doi.org/10.1001/jamaoncol.2015.1377
Mima, Kosuke ; Sukawa, Yasutaka ; Nishihara, Reiko ; Qian, Zhi Rong ; Yamauchi, Mai ; Inamura, Kentaro ; Kim, Sun A. ; Masuda, Atsuhiro ; Nowak, Jonathan A. ; Nosho, Katsuhiko ; Kostic, Aleksandar D. ; Giannakis, Marios ; Watanabe, Hideo ; Bullman, Susan ; Milner, Danny A. ; Harris, Curtis C. ; Giovannucci, Edward ; Garraway, Levi A. ; Freeman, Gordon J. ; Dranoff, Glenn ; Chan, Andrew T. ; Garrett, Wendy S. ; Huttenhower, Curtis ; Fuchs, Charles S. ; Ogino, Shuji. / Fusobacterium nucleatum and T cells in colorectal carcinoma. In: JAMA Oncology. 2015 ; Vol. 1, No. 5. pp. 653-661.
@article{7bee120d1a4147a480bc3b7834a550c1,
title = "Fusobacterium nucleatum and T cells in colorectal carcinoma",
abstract = "Importance: 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. Design, Setting, and Participants: A cross-sectional analysiswas 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. Main Outcomes and Measures: 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 for trend = .24, .88, and .014, respectively). Conclusions and Relevance: 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.",
author = "Kosuke Mima and Yasutaka Sukawa and Reiko Nishihara and Qian, {Zhi Rong} and Mai Yamauchi and Kentaro Inamura and Kim, {Sun A.} and Atsuhiro Masuda and Nowak, {Jonathan A.} and Katsuhiko Nosho and Kostic, {Aleksandar D.} and Marios Giannakis and Hideo Watanabe and Susan Bullman and Milner, {Danny A.} and Harris, {Curtis C.} and Edward Giovannucci and Garraway, {Levi A.} and Freeman, {Gordon J.} and Glenn Dranoff and Chan, {Andrew T.} and Garrett, {Wendy S.} and Curtis Huttenhower and Fuchs, {Charles S.} and Shuji Ogino",
note = "Funding Information: Author Contributions: Drs Mima and Ogino had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Mima, Harris, Chan, Garrett, Huttenhower, Fuchs, Ogino. Acquisition, analysis, or interpretation of data: Mima, Sukawa, Nishihara, Qian, Yamauchi, Inamura, Kim, Masuda, Nowak, Nosho, Kostic, Giannakis, Watanabe, Bullman, Milner, Giovannucci, Garraway, Freeman, Dranoff, Chan, Garrett, Fuchs, Ogino. Drafting of the manuscript: Mima, Chan, Ogino. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Mima, Nishihara, Giovannucci, Ogino. Obtained funding: Chan, Huttenhower, Fuchs, Ogino Administrative, technical, or material support: Nishihara, Kim, Masuda, Nosho, Kostic, Watanabe, Chan, Garrett, Fuchs, Ogino. Study supervision: Qian, Milner, Harris, Chan, Huttenhower, Fuchs, Ogino. Conflict of Interest Disclosures: Dr Chan previously served as a consultant for Bayer Healthcare, Millennium Pharmaceuticals, Pozen Inc, and Pfizer Inc. No other disclosures are reported. Funding/Support: This work was supported by National Institutes of Health (NIH) grants (P01 CA87969 to S. E. Hankinson, UM1 CA186107 to M. J. Stampfer, P01 CA55075 and UM1 CA167552 to W. C. Willett, K07 CA190673 to Dr Nishihara, R01 CA137178 to Dr Chan, P50 CA127003 to Dr Fuchs, R01 CA151993 to Dr Ogino) and by grants from the Paula and Russell Agrusa Fund for Colorectal Cancer Research, the Friends of the Dana-Farber Cancer Institute, Bennett Family Fund, and the Entertainment Industry Foundation through the National Colorectal Cancer Research Alliance. Dr Mima is supported by a fellowship grant from Uehara Memorial Foundation. Dr Kim is supported by an Early Exchange Postdoctoral Fellowship Grant from Asan Medical Center. Funding Information: This work was supported by National Institutes of Health (NIH) grants (P01 CA87969 to S. E. Hankinson, UM1 CA186107 to M. J. Stampfer, P01 CA55075 and UM1 CA167552 to W. C. Willett, K07 CA190673 to Dr Nishihara, R01 CA137178 to Dr Chan, P50 CA127003 to Dr Fuchs, R01 CA151993 to Dr Ogino) and by grants from the Paula and Russell Agrusa Fund for Colorectal Cancer Research, the Friends of the Dana-Farber Cancer Institute, Bennett Family Fund, and the Entertainment Industry Foundation through the National Colorectal Cancer Research Alliance. Dr Mima is supported by a fellowship grant from Uehara Memorial Foundation. Dr Kim is supported by an Early Exchange Postdoctoral Fellowship Grant from Asan Medical Center. Publisher Copyright: Copyright {\textcopyright} 2015 American Medical Association. All rights reserved.",
doi = "10.1001/jamaoncol.2015.1377",
journal = "JAMA oncology",
publisher = "American Medical Association",
T1 - Fusobacterium nucleatum and T cells in colorectal carcinoma
AU - Mima, Kosuke
AU - Sukawa, Yasutaka
AU - Nishihara, Reiko
AU - Qian, Zhi Rong
AU - Yamauchi, Mai
AU - Inamura, Kentaro
AU - Kim, Sun A.
AU - Masuda, Atsuhiro
AU - Nowak, Jonathan A.
AU - Nosho, Katsuhiko
AU - Kostic, Aleksandar D.
AU - Giannakis, Marios
AU - Watanabe, Hideo
AU - Bullman, Susan
AU - Milner, Danny A.
AU - Harris, Curtis C.
AU - Giovannucci, Edward
AU - Garraway, Levi A.
AU - Freeman, Gordon J.
AU - Dranoff, Glenn
AU - Chan, Andrew T.
AU - Garrett, Wendy S.
AU - Huttenhower, Curtis
AU - Fuchs, Charles S.
AU - Ogino, Shuji
N1 - Funding Information: Author Contributions: Drs Mima and Ogino had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Mima, Harris, Chan, Garrett, Huttenhower, Fuchs, Ogino. Acquisition, analysis, or interpretation of data: Mima, Sukawa, Nishihara, Qian, Yamauchi, Inamura, Kim, Masuda, Nowak, Nosho, Kostic, Giannakis, Watanabe, Bullman, Milner, Giovannucci, Garraway, Freeman, Dranoff, Chan, Garrett, Fuchs, Ogino. Drafting of the manuscript: Mima, Chan, Ogino. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Mima, Nishihara, Giovannucci, Ogino. Obtained funding: Chan, Huttenhower, Fuchs, Ogino Administrative, technical, or material support: Nishihara, Kim, Masuda, Nosho, Kostic, Watanabe, Chan, Garrett, Fuchs, Ogino. Study supervision: Qian, Milner, Harris, Chan, Huttenhower, Fuchs, Ogino. Conflict of Interest Disclosures: Dr Chan previously served as a consultant for Bayer Healthcare, Millennium Pharmaceuticals, Pozen Inc, and Pfizer Inc. No other disclosures are reported. Funding/Support: This work was supported by National Institutes of Health (NIH) grants (P01 CA87969 to S. E. Hankinson, UM1 CA186107 to M. J. Stampfer, P01 CA55075 and UM1 CA167552 to W. C. Willett, K07 CA190673 to Dr Nishihara, R01 CA137178 to Dr Chan, P50 CA127003 to Dr Fuchs, R01 CA151993 to Dr Ogino) and by grants from the Paula and Russell Agrusa Fund for Colorectal Cancer Research, the Friends of the Dana-Farber Cancer Institute, Bennett Family Fund, and the Entertainment Industry Foundation through the National Colorectal Cancer Research Alliance. Dr Mima is supported by a fellowship grant from Uehara Memorial Foundation. Dr Kim is supported by an Early Exchange Postdoctoral Fellowship Grant from Asan Medical Center. Funding Information: This work was supported by National Institutes of Health (NIH) grants (P01 CA87969 to S. E. Hankinson, UM1 CA186107 to M. J. Stampfer, P01 CA55075 and UM1 CA167552 to W. C. Willett, K07 CA190673 to Dr Nishihara, R01 CA137178 to Dr Chan, P50 CA127003 to Dr Fuchs, R01 CA151993 to Dr Ogino) and by grants from the Paula and Russell Agrusa Fund for Colorectal Cancer Research, the Friends of the Dana-Farber Cancer Institute, Bennett Family Fund, and the Entertainment Industry Foundation through the National Colorectal Cancer Research Alliance. Dr Mima is supported by a fellowship grant from Uehara Memorial Foundation. Dr Kim is supported by an Early Exchange Postdoctoral Fellowship Grant from Asan Medical Center. Publisher Copyright: Copyright © 2015 American Medical Association. All rights reserved.
N2 - Importance: 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. Design, Setting, and Participants: A cross-sectional analysiswas 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. Main Outcomes and Measures: 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 for trend = .24, .88, and .014, respectively). Conclusions and Relevance: 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.
AB - Importance: 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. Design, Setting, and Participants: A cross-sectional analysiswas 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. Main Outcomes and Measures: 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 for trend = .24, .88, and .014, respectively). Conclusions and Relevance: 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.
U2 - 10.1001/jamaoncol.2015.1377
DO - 10.1001/jamaoncol.2015.1377
JO - JAMA oncology
JF - JAMA oncology