Tumour budding, poorly differentiated clusters, and T-cell response in colorectal cancer
Kenji Fujiyoshi,
Juha P. Väyrynen,
Jennifer Borowsky,
David J. Papke, Jr.,
Kota Arima,
Koichiro Haruki,
Junko Kishikawa,
Naohiko Akimoto,
Tomotaka Ugai,
Mai Chan Lau,
Simeng Gu,
Shanshan Shi,
Melissa Zhao,
Annacarolina Fabiana Lucia Da Silva,
Tyler S. Twombly,
Hongmei Nan,
Jeffrey A. Meyerhardt,
Mingyang Song,
Xuehong Zhang,
Kana Wu,
Andrew T. Chan,
Charles S. Fuchs,
Jochen K. Lennerz,
Marios Giannakis,
Jonathan A. Nowak,
Shuji Ogino
Affiliations
Kenji Fujiyoshi
Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Department of Surgery, Kurume University, Kurume, Fukuoka, Japan
Juha P. Väyrynen
Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA; Cancer and Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital, and University of Oulu, Oulu, Finland
Jennifer Borowsky
Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
David J. Papke, Jr.
Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts, USA
Kota Arima
Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
Koichiro Haruki
Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
Junko Kishikawa
Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
Naohiko Akimoto
Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
Tomotaka Ugai
Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
Mai Chan Lau
Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
Simeng Gu
Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
Shanshan Shi
Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
Melissa Zhao
Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
Annacarolina Fabiana Lucia Da Silva
Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
Tyler S. Twombly
Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
Hongmei Nan
Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, Illinois, USA; Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Illinois, USA
Jeffrey A. Meyerhardt
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA
Mingyang Song
Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA; Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
Xuehong Zhang
Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
Kana Wu
Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
Andrew T. Chan
Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA; Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA
Charles S. Fuchs
Yale Cancer Center, New Haven, Connecticut, USA; Department of Medicine, Yale School of Medicine, New Haven, Connecticut, USA; Smilow Cancer Hospital, New Haven, Connecticut, USA
Jochen K. Lennerz
Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
Marios Giannakis
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
Jonathan A. Nowak
Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
Shuji Ogino
Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA; Cancer Immunology and Cancer Epidemiology Programs, Dana-Farber Harvard Cancer Center, Boston, Massachusetts, USA; Corresponding author at: Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Ave., EBRC Room 404A, Boston, Massachusetts 02115, USA .
Background: 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.
