Frei, A. L. et al. (2024) Multiplex analysis of intratumoural immune infiltrate and prognosis in patients with stage II–III colorectal cancer from the SCOT and QUASAR 2 trials: A retrospective analysis. Lancet Oncology, 25(2), pp. 198-211. (doi: 10.1016/S1470-2045(23)00560-0) (PMID:38301689)
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Abstract
Background Tumour-infiltrating CD8+ cytotoxic T cells confer favourable prognosis in colorectal cancer. The added prognostic value of other infiltrating immune cells is unclear and so we sought to investigate their prognostic value in two large clinical trial cohorts. Methods We used multiplex immunofluorescent staining of tissue microarrays to assess the densities of CD8+, CD20+, FoxP3+, and CD68+ cells in the intraepithelial and intrastromal compartments from tumour samples of patients with stage II–III colorectal cancer from the SCOT trial (ISRCTN59757862), which examined 3 months versus 6 months of adjuvant oxaliplatin-based chemotherapy, and from the QUASAR 2 trial (ISRCTN45133151), which compared adjuvant capecitabine with or without bevacizumab. Both trials included patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0–1. Immune marker predictors were analysed by multiple regression, and the prognostic and predictive values of markers for colorectal cancer recurrence-free interval by Cox regression were assessed using the SCOT cohort for discovery and QUASAR 2 cohort for validation. Findings After exclusion of cases without tissue microarrays and with technical failures, and following quality control, we included 2340 cases from the SCOT trial and 1069 from the QUASAR 2 trial in our analysis. Univariable analysis of associations with recurrence-free interval in cases from the SCOT trial showed a strong prognostic value of intraepithelial CD8 (CD8IE) as a continuous variable (hazard ratio [HR] for 75th vs 25th percentile [75vs25] 0·73 [95% CI 0·68–0·79], p=2·5 × 10−16), and of intrastromal FoxP3 (FoxP3IS; 0·71 [0·64–0·78], p=1·5 × 10−13) but not as strongly in the epithelium (FoxP3IE; 0·89 [0·84–0·96], p=1·5 × 10−4). Associations of other markers with recurrence-free interval were moderate. CD8IE and FoxP3IS retained independent prognostic value in bivariable and multivariable analysis, and, compared with either marker alone, a composite marker including both markers (CD8IE-FoxP3IS) was superior when assessed as a continuous variable (adjusted [a]HR75 vs 25 0·70 [95% CI 0·63–0·78], p=5·1 × 10−11) and when categorised into low, intermediate, and high density groups using previously published cutpoints (aHR for intermediate vs high 1·68 [95% CI 1·29–2·20], p=1·3 × 10−4; low vs high 2·58 [1·91–3·49], p=7·9 × 10−10), with performance similar to the gold-standard Immunoscore. The prognostic value of CD8IE-FoxP3IS was confirmed in cases from the QUASAR 2 trial, both as a continuous variable (aHR75 vs 25 0·84 [95% CI 0·73–0·96], p=0·012) and as a categorical variable for low versus high density (aHR 1·80 [95% CI 1·17–2·75], p=0·0071) but not for intermediate versus high (1·30 [0·89–1·88], p=0·17). Interpretation Combined evaluation of CD8IE and FoxP3IS could help to refine risk stratification in colorectal cancer. Investigation of FoxP3IS cells as an immunotherapy target in colorectal cancer might be merited.
| Item Type: | Articles |
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| Additional Information: | The SCOT trial was funded by the Medical Research Council (transferred to NETSCC–Efficacy and Mechanism Evaluation; grant number G0601705), the National Institute for Health and Care Research (NIHR) Health Technology Assessment (14/140/84), Cancer Research UK Core Clinical Trials Unit Glasgow funding (C6716/A9894), and the Swedish Cancer Society. The TransSCOT sample collection was funded by a Cancer Research UK Clinical Trials Awards and Advisory Committee—Sample Collection (C6716/A13941). The QUASAR 2 trial was funded by an unrestricted educational grant to DJK from Roche. This biomarker study was funded by the Oxford NIHR Comprehensive Biomedical Research Centre, a Cancer Research UK Advanced Clinician Scientist Fellowship (C26642/A27963) to DC, Cancer Research UK (award A25142) to the Cancer Research UK Glasgow Centre. VHK acknowledges funding by the Promedica Foundation (F-87701-41-01). |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Edwards, Professor Joanne and Oien, Professor Karin and Domingo, Dr Enric and Kelly, Mrs Caroline and Sansom, Professor Owen |
| Creator Roles: | Oien, K.Data curation, Resources Edwards, J.Resources Sansom, O.Funding acquisition, Resources Kelly, C.Resources Domingo, E.Data curation, Formal analysis, Resources, Visualization |
| Authors: | Frei, A. L., McGuigan, A., Sinha, R. R.A.K., Jabbar, F., Gneo, L., Tomasevic, T., Iveson, T., Saunders, M. P., Oien, K. A., Maka, N., Pezzella, F., Campo, L., Browne, M., Glaire, M., Kildal, W., Danielsen, H. E., Hay, J., Edwards, J., Sansom, O., Kelly, C., Tomlinson, I., Kerr, R., Kerr, D., Domingo, E., TransSCOT consortium, , Church, D. N., and Koelze, V. H. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing |
| Journal Name: | Lancet Oncology |
| Publisher: | Elsevier |
| ISSN: | 1470-2045 |
| ISSN (Online): | 1474-5488 |
| Copyright Holders: | Copyright: © 2024 The Author(s) |
| First Published: | First published in Lancet Oncology 25(2): 198-211 |
| Publisher Policy: | Reproduced under a Creative Commons licence |
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