TY - JOUR
T1 - Prognostic Value of T-Cell Density in the Tumor Center and Outer Margins in Gastric Cancer
AU - Soeratram, Tanya T. D.
AU - Biesma, Hedde D.
AU - Egthuijsen, Jacqueline M. P.
AU - Meershoek-Klein Kranenbarg, Elma
AU - Hartgrink, Henk H.
AU - van de Velde, Cornelis J. H.
AU - Mookhoek, Aart
AU - van Dijk, Erik
AU - Kim, Yongsoo
AU - Ylstra, Bauke
AU - van Laarhoven, Hanneke W. M.
AU - van Grieken, Nicole C. T.
N1 - Funding Information: The authors thank the Dutch National Tissuebank Portal for facilitating the collection of archival tumor formalin-fixed and paraffin-embedded samples from patients with GC who participated in the Dutch D1/D2 trial. Conceptualization: T.S. N.v.G. B.Y. and H.v.L.; Methodology: T.S. N.v.G. B.Y. H.v.L. A.M. Y.K. and E.v.D.; Formal analysis: T.S. and H.B.; Investigation: T.S. H.B. J.E. and N.v.G.; Resources (patients): H.H. and C.v.d.V.; Data curation: N.v.G. and E.M.; Visualization: T.S.; Funding acquisition: N.v.G. H.v.L. and B.Y.; Project administration: N.v.G.; Supervision: N.v.G. B.Y. and H.v.L.; Writing – original draft: T.S.; Writing – review and editing: all authors. All authors read and approved the final version of the manuscript. Anonymized data are available from the corresponding author upon reasonable request. This work was supported by the Dutch Cancer Society (grant number KWF10613). The authors declare no conflicts of interest. This study was performed in accordance with the Declaration of Helsinki. The D1/D2 trial was approved by the medical ethical committee of the Leiden University Medical Center. The Dutch Code of Conduct for Responsible Use of Human Tissue allows for the analysis of residual tissue specimens obtained for diagnostic purposes and anonymized publication of the study results. Funding Information: This work was supported by the Dutch Cancer Society (grant number KWF10613). Publisher Copyright: © 2023 The Authors
PY - 2023/9/1
Y1 - 2023/9/1
N2 - Tumor-infiltrating lymphocytes are associated with the survival of gastric cancer patients. T-cell densities in the tumor and its periphery were previously identified as prognostic T-cell markers for resectable gastric cancer. Immunohistochemistry for 5 T-cell markers, CD3, CD45RO, CD8, FOXP3, and granzyme B was performed on serial sections of N = 251 surgical resection specimens of patients treated with surgery only in the D1/D2 trial. Positive T cells were digitally quantified into tiles of 0.25 mm 2 across 3 regions: the tumor center (TC), the inner invasive margin, and the outer invasive margin (OIM). A classification and regression tree model was employed to identify the optimal combination of median T-cell densities per region with cancer-specific survival (CSS) as the outcome. All statistical tests were 2-sided. CD8 OIM was identified as the most dominant prognostic factor, followed by FOXP3 TC, resulting in a decision tree containing 3 prognostically distinct subgroups with high (Hi) or low (Lo) density of the markers: CD8 OIM Hi, CD8 OIM Lo/FOXP3 TC Hi, and CD8 OIM Lo/FOXP3 TC Lo. In a multivariable Cox regression analysis, which included pathological T and N stages, Lauren histologic types, EBV status, microsatellite instability, and type of surgery, the immune subgroups were independent predictors for CSS. CSS was lower for CD8 OIM Lo/FOXP3 TC Hi (HR: 5.02; 95% CI: 2.03-12.42) and for CD8 OIM Lo/FOXP3 TC Lo (HR: 7.99; 95% CI: 3.22-19.86), compared with CD8 OIM Hi (P <.0001). The location and density of both CD8 + and FOXP3 + T cells in resectable gastric cancer are independently associated with survival. The combination of CD8 OIM and FOXP3 TC T-cell densities is a promising stratification factor that should be validated in independent studies.
AB - Tumor-infiltrating lymphocytes are associated with the survival of gastric cancer patients. T-cell densities in the tumor and its periphery were previously identified as prognostic T-cell markers for resectable gastric cancer. Immunohistochemistry for 5 T-cell markers, CD3, CD45RO, CD8, FOXP3, and granzyme B was performed on serial sections of N = 251 surgical resection specimens of patients treated with surgery only in the D1/D2 trial. Positive T cells were digitally quantified into tiles of 0.25 mm 2 across 3 regions: the tumor center (TC), the inner invasive margin, and the outer invasive margin (OIM). A classification and regression tree model was employed to identify the optimal combination of median T-cell densities per region with cancer-specific survival (CSS) as the outcome. All statistical tests were 2-sided. CD8 OIM was identified as the most dominant prognostic factor, followed by FOXP3 TC, resulting in a decision tree containing 3 prognostically distinct subgroups with high (Hi) or low (Lo) density of the markers: CD8 OIM Hi, CD8 OIM Lo/FOXP3 TC Hi, and CD8 OIM Lo/FOXP3 TC Lo. In a multivariable Cox regression analysis, which included pathological T and N stages, Lauren histologic types, EBV status, microsatellite instability, and type of surgery, the immune subgroups were independent predictors for CSS. CSS was lower for CD8 OIM Lo/FOXP3 TC Hi (HR: 5.02; 95% CI: 2.03-12.42) and for CD8 OIM Lo/FOXP3 TC Lo (HR: 7.99; 95% CI: 3.22-19.86), compared with CD8 OIM Hi (P <.0001). The location and density of both CD8 + and FOXP3 + T cells in resectable gastric cancer are independently associated with survival. The combination of CD8 OIM and FOXP3 TC T-cell densities is a promising stratification factor that should be validated in independent studies.
KW - CD8-positive T cells
KW - FOXP3
KW - gastric cancer
KW - invasive margin
KW - prognostic marker
KW - regulatory T cells
KW - tumor-infiltrating lymphocytes
UR - http://www.scopus.com/inward/record.url?scp=85172423977&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.modpat.2023.100218
DO - https://doi.org/10.1016/j.modpat.2023.100218
M3 - Article
C2 - 37182582
SN - 0893-3952
VL - 36
SP - 100218
JO - Modern Pathology
JF - Modern Pathology
IS - 9
M1 - 100218
ER -