Fujiyoshi, K., Väyrynen, J. P., Borowsky, J., Papke, D. J., Jr., Arima, K., Haruki, K., Kishikawa, J., Akimoto, N., Ugai, T., Lau, M. C., Gu, S., Shi, S., Zhao, M., Da Silva, A. F. L., Twombly, T. S., Nan, H., Meyerhardt, J. A., Song, M., Zhang, X., … Ogino, S. (2020). Tumour budding, poorly differentiated clusters, and T-cell response in colorectal cancer. EBioMedicine, 57, 102860. https://doi.org/10.1016/j.ebiom.2020.102860
Tumour budding, poorly differentiated clusters, and T-cell response in colorectal cancer
|Author:||Fujiyoshi, Kenji1,2; Väyrynen, Juha P.1,3,4; Borowsky, Jennifer1;|
1Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
2Department of Surgery, Kurume University, Kurume, Fukuoka, Japan
3Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA
4Cancer and Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital, and University of Oulu, Oulu, Finland
5Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts, USA
6Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, Illinois, USA
7Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Illinois, USA
8Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
9Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA
10Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
11Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
12Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
13Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA
14Yale Cancer Center, New Haven, Connecticut, USA
15Department of Medicine, Yale School of Medicine, New Haven, Connecticut, USA
16Smilow Cancer Hospital, New Haven, Connecticut, USA
17Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
18Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
19Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
20Cancer Immunology and Cancer Epidemiology Programs, Dana-Farber Harvard Cancer Center, Boston, Massachusetts, USA
|Online Access:||PDF Full Text (PDF, 1.9 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe2020082061135
|Publish Date:|| 2020-08-20
Background/Objectives: Tumour budding and poorly differentiated clusters (PDC) represent forms of tumour invasion. We hypothesised that T-cell densities (reflecting adaptive anti-tumour immunity) might be inversely associated with tumour budding and PDC in colorectal carcinoma.
Methods: Utilising 915 colon and rectal carcinomas in two U.S.-wide prospective cohort studies, and multiplex immunofluorescence combined with machine learning algorithms, we assessed CD3, CD4, CD8, CD45RO (PTPRC), and FOXP3 co-expression patterns in lymphocytes. Tumour budding and PDC at invasive fronts were quantified by digital pathology and image analysis using the International tumour Budding Consensus Conference criteria. Using covariate data of 4,420 incident colorectal cancer cases, inverse probability weighting (IPW) was integrated with multivariable logistic regression analysis that assessed the association of T-cell subset densities with tumour budding and PDC while adjusting for selection bias due to tissue availability and potential confounders, including microsatellite instability status.
Findings: Tumour budding counts were inversely associated with density of CD3+CD8+ [lowest vs. highest: multivariable odds ratio (OR), 0.50; 95% confidence interval (CI), 0.35–0.70; Ptrend < 0.001] and CD3+CD8+CD45RO+ cells (lowest vs. highest: multivariable OR, 0.44; 95% CI, 0.31–0.63; Ptrend < 0.001) in tumour epithelial region. Tumour budding levels were associated with higher colorectal cancer-specific mortality (multivariable hazard ratio, 2.13; 95% CI, 1.57–2.89; Ptrend < 0.001) in Cox regression analysis. There were no significant associations of PDC with T-cell subsets.
Interpretation: Tumour epithelial naïve and memory cytotoxic T cell densities are inversely associated with tumour budding at invasive fronts, suggesting that cytotoxic anti-tumour immunity suppresses tumour microinvasion.
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
This work was supported by U.S. National Institutes of Health (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.F.; R01 CA118553 to C.S.F.; R01 CA169141 to C.S.F.; R01 CA137178 to A.T.C.; K24 DK098311 to A.T.C.; R35 CA197735 to S.O.; R01 CA151993 to S.O.; R01 CA248857 to S.O.; K07 CA188126 to X.Z., and R01 CA225655 to J.K.L.); by Nodal Award (2016–20) from the Dana-Farber Harvard Cancer Centre (to S.O.); by Stand Up to Cancer Colorectal Cancer Dream Team Translational Research Grant (SU2C-AACR-DT22–17 to C.S.F. and M.G.), administered by the American Association for Cancer Research, a scientific partner of SU2C; and by 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. K.F. was supported by fellowship grants from the Uehara Memorial Foundation and Grant of The Clinical Research Promotion Foundation (2018). K.A. and T.U. were supported by a grant from Overseas Research Fellowship (201860083 to K.A.; 201960541 to T.U.) from Japan Society for the Promotion of Science. K.H. was supported by fellowship grants from the Uehara Memorial Foundation and the Mitsukoshi Health and Welfare Foundation. J.A.M. research is 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.G. is supported by an ASCO Conquer Cancer Foundation Career Development Award. A.T.C. is a Stuart and Suzanne Steele MGH Research Scholar. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
© 2020 Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license. (http://creativecommons.org/licenses/by-nc-nd/4.0/)