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)

Luca G Campana; Wasat Mansoor; James Hill; Christian Macutkiewicz; Finlay Curran; David Donnelly; Ben Hornung; Peter Charleston; Robert Bristow; Graham M Lord; Sara Valpione

doi:10.3390/cancers14235883

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)

Cancers (Basel). 2022 Nov 29;14(23):5883. doi: 10.3390/cancers14235883.

Authors

Luca G Campana¹, Wasat Mansoor^{2

3}, James Hill¹, Christian Macutkiewicz¹, Finlay Curran¹, David Donnelly¹, Ben Hornung¹, Peter Charleston¹, Robert Bristow^{3

4}, Graham M Lord⁵, Sara Valpione^{2

6}

Affiliations

¹ Department of Surgery, Manchester University NHS Foundation Trust, Manchester M13 9WL, UK.
² Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK.
³ Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9NT, UK.
⁴ CRUK Manchester Major Centre and Manchester Cancer Research Centre, Manchester M20 4BX, UK.
⁵ Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK.
⁶ CRUK Manchester Institute, University of Manchester, Manchester SK10 4TG, UK.

Abstract

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.

Keywords: T-cell antigen receptor; colorectal neoplasms; nomograms; prognostic factors; prognostic model.

Grants and funding

This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.