Computational Image Analysis of T-Cell Infiltrates in Resectable Gastric Cancer: Association with Survival and Molecular Subtypes
Open Access
- 1 January 2021
- journal article
- research article
- Published by Oxford University Press (OUP) in JNCI Journal of the National Cancer Institute
- Vol. 113 (1), 88-98
- https://doi.org/10.1093/jnci/djaa051
Abstract
Background Gastric and gastro-esophageal junction cancers (GCs) frequently recur after resection, but markers to predict recurrence risk are missing. T-cell infiltrates have been validated as prognostic markers in other cancer types, but not in GC because of methodological limitations of past studies. We aimed to define and validate the prognostic role of major T-cell subtypes in GC by objective computational quantification. Methods Surgically resected chemotherapy-naive GCs were split into discovery (n=327) and validation (n=147) cohorts. CD8 (cytotoxic), CD45RO (memory), and FOXP3 (regulatory) T-cell densities were measured through multicolor immunofluorescence and computational image analysis. Cancer-specific survival (CSS) was assessed. All statistical tests were two-sided. Results CD45RO-cell and FOXP3-cell densities statistically significantly predicted CSS in both cohorts. Stage, CD45RO-cell, and FOXP3-cell densities were independent predictors of CSS in multivariable analysis; mismatch repair (MMR) and Epstein-Barr virus (EBV) status were not statistically significant. Combining CD45RO-cell and FOXP3-cell densities into the Stomach Cancer Immune Score showed highly statistically significant (all P <=.002) CSS differences (0.9years median CSS to not reached). T-cell infiltrates were highest in EBV-positive GCs and similar in MMR-deficient and MMR-proficient GCs. Conclusion The validation of CD45RO-cell and FOXP3-cell densities as prognostic markers in GC may guide personalized follow-up or (neo)adjuvant treatment strategies. Only those 20% of GCs with the highest T-cell infiltrates showed particularly good CSS, suggesting that a small subgroup of GCs is highly immunogenic. The potential for T-cell densities to predict immunotherapy responses should be assessed. The association of high FOXP3-cell densities with longer CSS warrants studies into the biology of regulatory T cells in GC.Funding Information
- Cancer Research UK
- Schottlander Foundation
- European Research Council under the European Union’s Horizon 2020 research and innovation program (820137)
- Royal Marsden Hospital/ICR NIHR Biomedical Research Centre for Cancer
This publication has 33 references indexed in Scilit:
- Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomesNature Medicine, 2015
- PD-1 blockade induces responses by inhibiting adaptive immune resistanceNature, 2014
- Signatures of tumour immunity distinguish Asian and non-Asian gastric adenocarcinomasGut, 2014
- Comprehensive molecular characterization of gastric adenocarcinomaNature, 2014
- Prognostic Value of Tumor-Infiltrating FoxP3+ T Cells in Gastrointestinal Cancers: A Meta AnalysisPLOS ONE, 2014
- Prognostic and Predictive Values of the Immunoscore in Patients with Rectal CancerClinical Cancer Research, 2014
- The Prognostic Value of FoxP3+ Tumor-Infiltrating Lymphocytes in Cancer: A Critical Review of the LiteratureClinical Cancer Research, 2012
- The immune score as a new possible approach for the classification of cancerJournal of Translational Medicine, 2012
- Human T cells express CD25 and Foxp3 upon activation and exhibit effector/memory phenotypes without any regulatory/suppressor functionJournal of Translational Medicine, 2009
- Type, Density, and Location of Immune Cells Within Human Colorectal Tumors Predict Clinical OutcomeScience, 2006