T 细胞浸润与克隆性可识别结直肠癌中不同的生存组：基于癌症基因组图谱（TCGA）和临床蛋白质组肿瘤分析联盟（CPTAC）的预后模型构建与验证

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.