Prognostic Value of CD8+ T-Cells at the Invasive Margin is Comparable to Immune Score in Non-Metastatic Colorectal Cancer: Prospective Multicenter Cohort Study

Abstract Background The Immunoscore® is a validated tool for predicting colorectal cancer (CRC) prognosis, yet its adoption is impeded by complex commercial software and patient reimbursement challenges. Utilizing open-source methods, this study aimed to explore whether an immune cell score can be facilitated by focusing on single T-cell markers, to provide a simplified prognostic model in non-metastatic CRC. Methods A multicentric prospective cohort study was conducted in non-metastatic CRC patients who underwent curative surgical resection. CD3+ and CD8+ tumor infiltrating lymphocytes (TILs) were quantified in both invasive margin (IM) and tumor core (TC) using QuPath. A composite score, termed immune cell score, mirroring the methods employed for the Immunoscore®, was calculated based on the TIL densities (CD3-IM, CD8-IM, CD3-TC, CD8-TC]. We used a split sample approach (70:30) to estimate adjusted hazard ratios of cancer-specific survival (CSS) in a training and a validation set. Classification and regression tree analysis (CART) was performed to select the most prognostic TIL. The model incorporating the CART-selected TIL was compared to a two-tiered immune cell score model for overall performance (Brier score) and discrimination (concordance probability estimate, CPE). Results During a median follow-up time of 9.0 years, among 1260 patients, there were 203 CRC specific deaths. CART-selected CD8-IM was the most prognostic TIL at a cut-off of 231 cells/mm2. Patients with CD8-IM Hi had better CSS than CD8-IM Low in both training (HR 0.58, 95% CI 0.40-0.84) and validation sets (HR 0.35, 95% CI 0.21-0.60). Brier scores of CD-8IM and immune cell score survival models were comparable in both training and validation cohort, whereas the survival discrimination of CD8-IM slightly outperformed the immune cell score in the validation set (CPE: CD8-IM 0.748, IS 0.730). Conclusion A single TIL marker, specifically CD8-IM, provided prognostic information comparable to the immune cell score. Simplified and cost-effective TIL assessments could enhance their bench to bedside translation and may guide adjuvant therapy in early-stage CRC.