The density of tumour infiltrating lymphocytes in oesophago-gastric cancer varies with disease stage, geographical region and treatment: a post hoc analysis of nine phase III clinical trials

Georgina A. Keogh; Nina Šefčovičová; Tomio Arai; Myeong Cherl Kook; Jon P. Laye; William H. Allum; Sameira Arif; Avani Athauda; Hee Kyung Chang; Jae Ho Cheong; Mee Yon Cho; David Cunningham; Lara Heij; Andrew F. Irvine; Hee Sung Kim; Hyunki Kim; Young Woo Kim; Ruth E. Langley; Sung Hak Lee; Katharina von Loga; Matthew G. Nankivell; Takashi Oshima; Russell D. Petty; Xiuxiang Tan; Shiro Tanaka; Akira Tsuburaya; Judith de Vos-Geelen; Nicholas P. West; Jake Emmerson; Jamie R. Stokes; Derek R. Magee; David A. Cairns; Heike I. Grabsch

doi:10.1007/s10120-026-01739-6

The density of tumour infiltrating lymphocytes in oesophago-gastric cancer varies with disease stage, geographical region and treatment: a post hoc analysis of nine phase III clinical trials

Georgina A. Keogh
, Nina Šefčovičová
, Tomio Arai
, Myeong Cherl Kook
, Jon P. Laye
, William H. Allum
, Sameira Arif
, Avani Athauda
, Hee Kyung Chang
, Jae Ho Cheong
, Mee Yon Cho
, David Cunningham
, Lara Heij
, Andrew F. Irvine
, Hee Sung Kim
, Hyunki Kim
, Young Woo Kim
, Ruth E. Langley
, Sung Hak Lee
, Katharina von Loga

Matthew G. Nankivell, Takashi Oshima, Russell D. Petty, Xiuxiang Tan, Shiro Tanaka, Akira Tsuburaya, Judith de Vos-Geelen, Nicholas P. West, Jake Emmerson, Jamie R. Stokes, Derek R. Magee, David A. Cairns, Heike I. Grabsch (Lead / Corresponding author)

Cancer Research

Research output: Contribution to journal › Article › peer-review

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Abstract

Background: Tumour infiltrating lymphocytes (TILs) are a key component of the tumour microenvironment. To establish a clinically relevant TILs cut-off for patients with oesophago-gastric (OG) cancer, it is essential to know whether TILs density varies by patient and/or disease characteristics. Materials and methods: TILs were quantified as TILs/mm² (TILs density) by a deep-learning algorithm applied to digitised Haematoxylin/Eosin (H&E)-stained biopsies and resection specimens from 4628 patients from nine phase III trials. 4533 patients with TILs density and matched clinicopathological data were included in the final analyses. Associations between TILs density, disease stage, geographical region (UK versus Asia), sex, age, and treatment were analysed. Results: Median TILs density was higher in pre-treatment biopsies from patients with early-stage versus late-stage disease (962 vs 479 TILs/mm², p < 0.001). Within the same geographical region and disease stage, TILs density was similar across different chemotherapy regimens. In UK-led trials of early-stage disease, post-chemotherapy resections showed higher TILs density than chemotherapy-naïve resections (618 vs 571 TILs/mm², p = 0.003). TILs density was higher in Asian tumours compared to UK tumours (1419 vs 571 TILs/mm², p < 0.001). No significant associations were observed with age or sex. Conclusions: This is the largest study to date evaluating TILs density in OG cancer. TILs density varied with stage and geographical region but not by age or sex. These findings may explain enhanced response to immunotherapy observed in published studies of patients with early-stage disease and highlight the need to account for baseline TILs heterogeneity when interpreting TILs as a possible biomarker in future studies.

Original language	English
Journal	Gastric Cancer
Early online date	5 May 2026
DOIs	https://doi.org/10.1007/s10120-026-01739-6
Publication status	E-pub ahead of print - 5 May 2026

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Age
Disease stage
Oesophago-gastric cancer
Sex
Treatment
Tumour infiltrating lymphocytes

ASJC Scopus subject areas

Oncology
Gastroenterology
Cancer Research

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Keogh, G. A., Šefčovičová, N., Arai, T., Kook, M. C., Laye, J. P., Allum, W. H., Arif, S., Athauda, A., Chang, H. K., Cheong, J. H., Cho, M. Y., Cunningham, D., Heij, L., Irvine, A. F., Kim, H. S., Kim, H., Kim, Y. W., Langley, R. E., Lee, S. H., ... Grabsch, H. I. (2026). The density of tumour infiltrating lymphocytes in oesophago-gastric cancer varies with disease stage, geographical region and treatment: a post hoc analysis of nine phase III clinical trials. Gastric Cancer. Advance online publication. https://doi.org/10.1007/s10120-026-01739-6

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title = "The density of tumour infiltrating lymphocytes in oesophago-gastric cancer varies with disease stage, geographical region and treatment: a post hoc analysis of nine phase III clinical trials",

abstract = "Background: Tumour infiltrating lymphocytes (TILs) are a key component of the tumour microenvironment. To establish a clinically relevant TILs cut-off for patients with oesophago-gastric (OG) cancer, it is essential to know whether TILs density varies by patient and/or disease characteristics. Materials and methods: TILs were quantified as TILs/mm2 (TILs density) by a deep-learning algorithm applied to digitised Haematoxylin/Eosin (H\&E)-stained biopsies and resection specimens from 4628 patients from nine phase III trials. 4533 patients with TILs density and matched clinicopathological data were included in the final analyses. Associations between TILs density, disease stage, geographical region (UK versus Asia), sex, age, and treatment were analysed. Results: Median TILs density was higher in pre-treatment biopsies from patients with early-stage versus late-stage disease (962 vs 479 TILs/mm2, p < 0.001). Within the same geographical region and disease stage, TILs density was similar across different chemotherapy regimens. In UK-led trials of early-stage disease, post-chemotherapy resections showed higher TILs density than chemotherapy-na{\"i}ve resections (618 vs 571 TILs/mm2, p = 0.003). TILs density was higher in Asian tumours compared to UK tumours (1419 vs 571 TILs/mm2, p < 0.001). No significant associations were observed with age or sex. Conclusions: This is the largest study to date evaluating TILs density in OG cancer. TILs density varied with stage and geographical region but not by age or sex. These findings may explain enhanced response to immunotherapy observed in published studies of patients with early-stage disease and highlight the need to account for baseline TILs heterogeneity when interpreting TILs as a possible biomarker in future studies.",

keywords = "Age, Disease stage, Oesophago-gastric cancer, Sex, Treatment, Tumour infiltrating lymphocytes",

author = "Keogh, \{Georgina A.\} and Nina {\v S}ef{\v c}ovi{\v c}ov{\'a} and Tomio Arai and Kook, \{Myeong Cherl\} and Laye, \{Jon P.\} and Allum, \{William H.\} and Sameira Arif and Avani Athauda and Chang, \{Hee Kyung\} and Cheong, \{Jae Ho\} and Cho, \{Mee Yon\} and David Cunningham and Lara Heij and Irvine, \{Andrew F.\} and Kim, \{Hee Sung\} and Hyunki Kim and Kim, \{Young Woo\} and Langley, \{Ruth E.\} and Lee, \{Sung Hak\} and \{von Loga\}, Katharina and Nankivell, \{Matthew G.\} and Takashi Oshima and Petty, \{Russell D.\} and Xiuxiang Tan and Shiro Tanaka and Akira Tsuburaya and \{de Vos-Geelen\}, Judith and West, \{Nicholas P.\} and Jake Emmerson and Stokes, \{Jamie R.\} and Magee, \{Derek R.\} and Cairns, \{David A.\} and Grabsch, \{Heike I.\}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2026.",

year = "2026",

month = may,

day = "5",

doi = "10.1007/s10120-026-01739-6",

language = "English",

journal = "Gastric Cancer",

issn = "1436-3291",

publisher = "Springer",

}

Keogh, GA, Šefčovičová, N, Arai, T, Kook, MC, Laye, JP, Allum, WH, Arif, S, Athauda, A, Chang, HK, Cheong, JH, Cho, MY, Cunningham, D, Heij, L, Irvine, AF, Kim, HS, Kim, H, Kim, YW, Langley, RE, Lee, SH, von Loga, K, Nankivell, MG, Oshima, T, Petty, RD, Tan, X, Tanaka, S, Tsuburaya, A, de Vos-Geelen, J, West, NP, Emmerson, J, Stokes, JR, Magee, DR, Cairns, DA & Grabsch, HI 2026, 'The density of tumour infiltrating lymphocytes in oesophago-gastric cancer varies with disease stage, geographical region and treatment: a post hoc analysis of nine phase III clinical trials', Gastric Cancer. https://doi.org/10.1007/s10120-026-01739-6

TY - JOUR

T1 - The density of tumour infiltrating lymphocytes in oesophago-gastric cancer varies with disease stage, geographical region and treatment

T2 - a post hoc analysis of nine phase III clinical trials

AU - Keogh, Georgina A.

AU - Šefčovičová, Nina

AU - Arai, Tomio

AU - Kook, Myeong Cherl

AU - Laye, Jon P.

AU - Allum, William H.

AU - Arif, Sameira

AU - Athauda, Avani

AU - Chang, Hee Kyung

AU - Cheong, Jae Ho

AU - Cho, Mee Yon

AU - Cunningham, David

AU - Heij, Lara

AU - Irvine, Andrew F.

AU - Kim, Hee Sung

AU - Kim, Hyunki

AU - Kim, Young Woo

AU - Langley, Ruth E.

AU - Lee, Sung Hak

AU - von Loga, Katharina

AU - Nankivell, Matthew G.

AU - Oshima, Takashi

AU - Petty, Russell D.

AU - Tan, Xiuxiang

AU - Tanaka, Shiro

AU - Tsuburaya, Akira

AU - de Vos-Geelen, Judith

AU - West, Nicholas P.

AU - Emmerson, Jake

AU - Stokes, Jamie R.

AU - Magee, Derek R.

AU - Cairns, David A.

AU - Grabsch, Heike I.

PY - 2026/5/5

Y1 - 2026/5/5

N2 - Background: Tumour infiltrating lymphocytes (TILs) are a key component of the tumour microenvironment. To establish a clinically relevant TILs cut-off for patients with oesophago-gastric (OG) cancer, it is essential to know whether TILs density varies by patient and/or disease characteristics. Materials and methods: TILs were quantified as TILs/mm2 (TILs density) by a deep-learning algorithm applied to digitised Haematoxylin/Eosin (H&E)-stained biopsies and resection specimens from 4628 patients from nine phase III trials. 4533 patients with TILs density and matched clinicopathological data were included in the final analyses. Associations between TILs density, disease stage, geographical region (UK versus Asia), sex, age, and treatment were analysed. Results: Median TILs density was higher in pre-treatment biopsies from patients with early-stage versus late-stage disease (962 vs 479 TILs/mm2, p < 0.001). Within the same geographical region and disease stage, TILs density was similar across different chemotherapy regimens. In UK-led trials of early-stage disease, post-chemotherapy resections showed higher TILs density than chemotherapy-naïve resections (618 vs 571 TILs/mm2, p = 0.003). TILs density was higher in Asian tumours compared to UK tumours (1419 vs 571 TILs/mm2, p < 0.001). No significant associations were observed with age or sex. Conclusions: This is the largest study to date evaluating TILs density in OG cancer. TILs density varied with stage and geographical region but not by age or sex. These findings may explain enhanced response to immunotherapy observed in published studies of patients with early-stage disease and highlight the need to account for baseline TILs heterogeneity when interpreting TILs as a possible biomarker in future studies.

AB - Background: Tumour infiltrating lymphocytes (TILs) are a key component of the tumour microenvironment. To establish a clinically relevant TILs cut-off for patients with oesophago-gastric (OG) cancer, it is essential to know whether TILs density varies by patient and/or disease characteristics. Materials and methods: TILs were quantified as TILs/mm2 (TILs density) by a deep-learning algorithm applied to digitised Haematoxylin/Eosin (H&E)-stained biopsies and resection specimens from 4628 patients from nine phase III trials. 4533 patients with TILs density and matched clinicopathological data were included in the final analyses. Associations between TILs density, disease stage, geographical region (UK versus Asia), sex, age, and treatment were analysed. Results: Median TILs density was higher in pre-treatment biopsies from patients with early-stage versus late-stage disease (962 vs 479 TILs/mm2, p < 0.001). Within the same geographical region and disease stage, TILs density was similar across different chemotherapy regimens. In UK-led trials of early-stage disease, post-chemotherapy resections showed higher TILs density than chemotherapy-naïve resections (618 vs 571 TILs/mm2, p = 0.003). TILs density was higher in Asian tumours compared to UK tumours (1419 vs 571 TILs/mm2, p < 0.001). No significant associations were observed with age or sex. Conclusions: This is the largest study to date evaluating TILs density in OG cancer. TILs density varied with stage and geographical region but not by age or sex. These findings may explain enhanced response to immunotherapy observed in published studies of patients with early-stage disease and highlight the need to account for baseline TILs heterogeneity when interpreting TILs as a possible biomarker in future studies.

KW - Age

KW - Disease stage

KW - Oesophago-gastric cancer

KW - Sex

KW - Treatment

KW - Tumour infiltrating lymphocytes

UR - https://www.scopus.com/pages/publications/105037815789

U2 - 10.1007/s10120-026-01739-6

DO - 10.1007/s10120-026-01739-6

M3 - Article

C2 - 42084815

AN - SCOPUS:105037815789

SN - 1436-3291

JO - Gastric Cancer

JF - Gastric Cancer

ER -

The density of tumour infiltrating lymphocytes in oesophago-gastric cancer varies with disease stage, geographical region and treatment: a post hoc analysis of nine phase III clinical trials

Abstract

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Keywords

ASJC Scopus subject areas

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