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Enabling the examination of cell-cell relationships in tissue, spatially resolved omics technologies have revolutionised our perspectives on cancer biology. Clinically, the development of immune checkpoint inhibitors (ICI) has advanced cancer therapeutics. However, a major challenge of effective implementation is the identification of predictive biomarkers of response. In this review we examine the potential added predictive value of spatial biomarkers of response to ICI beyond current clinical benchmarks., (© 2024. The Author(s).)

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 (CD8 IE ) 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 (FoxP3 IS ; 0·71 [0·64-0·78], p=1·5 × 10 -13 ) but not as strongly in the epithelium (FoxP3 IE ; 0·89 [0·84-0·96], p=1·5 × 10 -4 ). Associations of other markers with recurrence-free interval were moderate. CD8 IE and FoxP3 IS retained independent prognostic value in bivariable and multivariable analysis, and, compared with either marker alone, a composite marker including both markers (CD8 IE -FoxP3 IS ) was superior when assessed as a continuous variable (adjusted [a]HR 75 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 CD8 IE -FoxP3 IS was confirmed in cases from the QUASAR 2 trial, both as a continuous variable (aHR 75 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 CD8 IE and FoxP3 IS could help to refine risk stratification in colorectal cancer. Investigation of FoxP3 IS cells as an immunotherapy target in colorectal cancer might be merited., Funding: Medical Research Council, National Institute for Health Research, Cancer Research UK, Swedish Cancer Society, Roche, and Promedica Foundation., Competing Interests: Declaration of interests DK has patents related to use of digital pathology algorithms, and serves as an advisor and has stock in Oxford Cancer Biomarkers. MPS has received honoraria from Merck, Server, Bayer, Takeda, and Amgen for meetings or lectures. WK has received royalties from Room4. DNC has participated in advisory boards for MSD and has received research funding on behalf of the TransSCOT consortium from HalioDx for analyses independent of this study. VHK has served as an invited speaker on behalf of Sharing Progress in Cancer Care and Indica Labs, and has received project-based research funding from The Image Analysis Group and Roche outside of the submitted work. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)