Automated deep learning-based assessment of tumour-infiltrating lymphocyte density determines prognosis in colorectal cancer

Millward, J; He, Z; Nibali, A; Mouradov, D; Mielke, LA; Tran, K; Chou, A; Hawkins, NJ; Ward, RL; Gill, AJ; Sieber, OM; Williams, DS

Author(s): Millward, J; He, Z; Nibali, A; Mouradov, D; Mielke, LA; Tran, K; Chou, A; Hawkins, NJ; Ward, RL; Gill, AJ; Sieber, OM; Williams, DS;
Details: Publication Year 2025-03-10,Volume 23,Issue #1,Page 298
Journal Title: Journal of Translational Medicine
Abstract: BACKGROUND: The presence of tumour-infiltrating lymphocytes (TILs) is a well-established prognostic biomarker across multiple cancer types, with higher TIL counts being associated with lower recurrence rates and improved patient survival. We aimed to examine whether an automated intraepithelial TIL (iTIL) assessment could stratify patients by risk, with the ability to generalise across independent patient cohorts, using routine H&E slides of colorectal cancer (CRC). To our knowledge, no other existing fully automated iTIL system has demonstrated this capability. METHODS: An automated method employing deep neural networks was developed to enumerate iTILs in H&E slides of CRC. The method was applied to a Stage III discovery cohort (n = 353) to identify an optimal threshold of 17 iTILs per-mm(2) tumour for stratifying relapse-free survival. Using this threshold, patients from two independent Stage II-III validation cohorts (n = 1070, n = 885) were classified as "TIL-High" or "TIL-Low". RESULTS: Significant stratification was observed in terms of overall survival for a combined validation cohort univariate (HR 1.67, 95%CI 1.39-2.00; p < 0.001) and multivariate (HR 1.37, 95%CI 1.13-1.66; p = 0.001) analysis. Our iTIL classifier was an independent prognostic factor within proficient DNA mismatch repair (pMMR) Stage II CRC cases with clinical high-risk features. Of these, those classified as TIL-High had outcomes similar to pMMR clinical low risk cases, and those classified TIL-Low had significantly poorer outcomes (univariate HR 2.38, 95%CI 1.57-3.61; p < 0.001, multivariate HR 2.17, 95%CI 1.42-3.33; p < 0.001). CONCLUSIONS: Our deep learning method is the first fully automated system to stratify patient outcome by analysing TILs in H&E slides of CRC, that has shown generalisation capabilities across multiple independent cohorts.
Publisher: BMC
Keywords: Humans; *Deep Learning; *Lymphocytes, Tumor-Infiltrating/immunology; *Colorectal Neoplasms/pathology/immunology/diagnosis; Prognosis; Female; Male; Middle Aged; Aged; Automation; Cohort Studies; Disease-Free Survival; Multivariate Analysis; Cell detection; Computational pathology; Image analysis; Tissue segmentation
Research Division(s): Personalised Oncology
PubMed ID: 40065354
Publisher's Version: https://doi.org/10.1186/s12967-025-06254-3
Open Access at Publisher's Site: https://doi.org/10.1186/s12967-025-06254-3
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-04-10 09:58:38

Last Modified: 2025-04-10 10:00:14