Transcriptome of Tumor-Infiltrating T Cells in Colorectal Cancer Patients Uncovered a Unique Gene Signature in CD4+ T Cells Associated with Poor Disease-Specific Survival.

Salman M Toor,Mohamed Abu Nada,Mahmood Al-Dhaheri,Khaled Murshed,Rowaida Z Taha,Reem Saleh,Eyad Elkord,Varun Sasidharan Nair,Ayman A Ahmed,Mohamed A Kurer,Mahwish Khawar

doi:10.3390/vaccines9040334

Abstract

Colorectal cancer (CRC) is influenced by infiltration of immune cell populations in the tumor microenvironment. While elevated levels of cytotoxic T cells are associated with improved prognosis, limited studies have reported associations between CD4+ T cells and disease outcomes. We recently performed transcriptomic profiling and comparative analyses of sorted CD4+ and CD8+ tumor-infiltrating lymphocytes (TILs) from bulk tumors of CRC patients with varying disease stages. In this study, we compared the transcriptomes of CD4+ with CD8+ TILs. Functional annotation pathway analyses revealed the downregulation of inflammatory response-related genes, while T cell activation and angiogenesis-related genes were upregulated in CD4+ TILs. The top 200 deregulated genes in CD4+ TILs were aligned with the cancer genome atlas (TCGA) CRC dataset to identify a unique gene signature associated with poor prognosis. Moreover, 69 upregulated and 20 downregulated genes showed similar trends of up/downregulation in the TCGA dataset and were used to calculate “poor prognosis score” (ppScore), which was significantly associated with disease-specific survival. High ppScore patients showed lower expression of Treg-, Th1-, and Th17-related genes, and higher expression of Th2-related genes. Our data highlight the significance of T cells within the TME and identify a unique candidate prognostic gene signature for CD4+ TILs in CRC patients.

Highlights

Global cancer statistics have ranked colorectal cancer (CRC) as the fourth most commonly diagnosed cancer and associated it with high mortality in both sexes combined [1]
The relationship between T regulatory cells (Tregs) and tumor progression in CRC is less clear; some studies suggested that high infiltration of FoxP3+ Tregs is associated with a favorable prognosis in CRC [7,8], while others reported the association of Tregs with a poor prognosis and attributed it to Treg heterogeneity [9,10]
Genes known to be expressed in CD4+ or CD8+ T cells were utilized as controls to co6nofif r1m6 the purity of the analyzed T cell subsets

Summary

Introduction

Global cancer statistics have ranked colorectal cancer (CRC) as the fourth most commonly diagnosed cancer and associated it with high mortality in both sexes combined (incidence; 6.1%, mortality; 9.2% of total cancer cases) [1]. The advent of novel therapeutic approaches, primarily in the form of immunotherapy, and improved screening technologies led to steady decrease in mortality rates of common cancers over the past few decades. These declines have slowed down or even halted for some cancers in recent years [2]. While elevated levels of tumor-infiltrating cytotoxic T cells (CTLs) are associated with improved prognosis and outcomes of CRC [11], limited studies have reported a significant association between CD4+ T cell infiltration and survival; possibly attributing it to the different subsets and heterogeneity of CD4+ T cell populations [12]. Galon et al, investigated CD3+ T cells and CD8+ CTLs in the center of a tumor and at the invasive margin, and reported the immunological data as a more robust survival predictor than the histopathological methods in clinical practice to segregate between CRC stages [14]

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Results

Conclusion