T-Cell Infiltration and Clonality May Identify Distinct Survival Groups in Colorectal Cancer: Development and Validation of a Prognostic Model Based on The Cancer Genome Atlas (TCGA) and Clinical Proteomic Tumor Analysis Consortium (CPTAC)

Predicting the survival outcomes of patients with colorectal cancer (CRC) remains challenging. We investigated the prognostic significance of the transcriptome and tumour-infiltrating lymphocyte T-cell receptor (TIL/Tc-TCR) repertoire and analysed TIL/Tc-TCR sequences of The Cancer Genome Atlas (TCGA) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) CRC cohorts. Using a multivariate Cox regression, we tested whether TIL/Tc-TCR repertoire, patient and tumour characteristics (stage, sidedness, total non-synonymous mutations, microsatellite instability (MSI) and transcriptional signatures) correlated with patient overall survival (OS) and designed a prognostic nomogram. A multivariate analysis (C-index = 0.75) showed that only patient age, disease stage, TIL/Tc degree of infiltration and clonality were independent prognostic factors for OS. The cut-offs for patients’ allocation to TIL/Tc abundance subgroups were determined using a strategy of maximally selected rank statistics with the OptimalCutpoints R package. These were “high”, “low” and “very high” (90 th percentile) TIL/Tc infiltration-stratified OS (median not reached, 67 and 44.3 months; p < 0.001); the results were validated in the CPTAC cohort. TIL/Tc clonality was prognostic (median OS in “high” vs. “low” clonality not reached and 67.3 months; p = 0.041) and independent of TIL/Tc infiltration. Whilst tumour sidedness was not prognostic, the “very highly” infiltrated tumours were prevalent among right-sided CRCs (p = 0.039) and showed distinct immunological features, with lower Th1 signature (p = 0.004), higher PD-L1 expression (p < 0.001) and likely enrichment in highly suppressory IL1R1 ⁺ Tregs (FoxP3 and IL1R1 overexpression, p < 0.001). TIL/Tc abundance and clonality are independent prognosticators in CRC and, combined with clinical variables, refine risk stratification. We identified a subset of CRCs with “very high” TIL/Tc infiltration, poor prognosis and distinct genetic and immunologic features, which may benefit from alternative therapeutic approaches. These results need validation in prospective patient cohorts.