Tumour budding, poorly differentiated clusters, and T-cell response in colorectal cancer.

TitleTumour budding, poorly differentiated clusters, and T-cell response in colorectal cancer.
Publication TypeJournal Article
Year of Publication2020
AuthorsFujiyoshi K, Väyrynen JP, Borowsky J, Papke DJ, Arima K, Haruki K, Kishikawa J, Akimoto N, Ugai T, Lau MChan, Gu S, Shi S, Zhao M, Da Silva AFabiana Lu, Twombly TS, Nan H, Meyerhardt JA, Song M, Zhang X, Wu K, Chan AT, Fuchs CS, Lennerz JK, Giannakis M, Nowak JA, Ogino S
JournalEBioMedicine
Volume57
Pagination102860
Date Published2020 Jul
ISSN2352-3964
KeywordsAdult, Aged, CD3 Complex, CD4 Antigens, CD8 Antigens, Colorectal Neoplasms, Female, Forkhead Transcription Factors, Humans, Leukocyte Common Antigens, Lymphocytes, Tumor-Infiltrating, Male, Middle Aged, Neoplasm Invasiveness, T-Lymphocyte Subsets
Abstract

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.

DOI10.1016/j.ebiom.2020.102860
Alternate JournalEBioMedicine
PubMed ID32652320
PubMed Central IDPMC7347996
Grant ListR35 CA197735 / CA / NCI NIH HHS / United States
R01 CA118553 / CA / NCI NIH HHS / United States
P01 CA087969 / CA / NCI NIH HHS / United States
R01 CA248857 / CA / NCI NIH HHS / United States
R37 CA225655 / CA / NCI NIH HHS / United States
U01 CA167552 / CA / NCI NIH HHS / United States
R01 CA137178 / CA / NCI NIH HHS / United States
K24 DK098311 / DK / NIDDK NIH HHS / United States
UM1 CA186107 / CA / NCI NIH HHS / United States
R01 CA169141 / CA / NCI NIH HHS / United States
P50 CA127003 / CA / NCI NIH HHS / United States
P01 CA055075 / CA / NCI NIH HHS / United States
R01 CA151993 / CA / NCI NIH HHS / United States
K07 CA188126 / CA / NCI NIH HHS / United States
UM1 CA167552 / CA / NCI NIH HHS / United States
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