RNA-Seq Analysis of Colorectal Tumor-Infiltrating Myeloid-Derived Suppressor Cell Subsets Revealed Gene Signatures of Poor Prognosis.

Mohamed Abu Nada,Nehad M Alajez,Eyad Elkord,Mahwish Khawar,Mahmood Al-Dhaheri,Varun Sasidharan Nair,Reem Saleh

doi:10.3389/fonc.2020.604906

Abstract

Elevated levels of myeloid-derived suppressor cells (MDSCs), including polymorphonuclear MDSCs (PMN-MDSCs) and immature MDSCs (I-MDSCs), are usually associated with disease progression in cancer patients, including colorectal cancer (CRC). However, biological mechanisms and molecular pathways regulated by MDSC subpopulations in the CRC tumor microenvironment (TME) have not been fully investigated. In this study, we performed transcriptomic analysis of tumor-infiltrating I-MDSCs and PMN-MDSCs isolated from tumor tissues of six CRC patients, compared to antigen-presenting cells (APCs). We also compared the transcriptomic profiles of tumor-infiltrating PMN-MDSCs to I-MDSCs. Our results showed different molecular pathways regulated by each MDSC subset, potentially reflecting their phenotypical/molecular/functional characteristics in the CRC TME. Moreover, we identified gene signatures in PMN-MDSC and I-MDSC of poor overall survival (OS) and disease-free survival (DFS) using the Cancer Genome Atlas (TCGA) dataset from patients with colon adenocarcinoma (COAD). However, functional studies are required to validate these findings.

Highlights

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of myeloid cells, halted at varying stages of maturation/differentiation and exert immunosuppressive activity on other immune cells [1, 2]
We found that immune response-mediated pathways associated with dendritic cell (DC) maturation [15], triggering receptor expressed on myeloid cells 1 (TREM1) signaling [16], nuclear factor of activated T cells (NFAT)-mediated regulation of immune response [17], and Fcg receptor-mediated phagocytosis [18] were commonly downregulated in PMNMDSCs and immature myeloid-derived suppressor cells (MDSCs) (I-MDSCs), compared to antigen-presenting cells (APCs)
We found that pathways related to TREM1 signaling, leukocyte extravasation, DC maturation, NFAT regulation of the immune response, Fcg receptor-mediated phagocytosis in macrophages and monocytes, IL-8 signaling, IL-6 signaling, Toll-like receptor signaling, LPS-mediated Mitogenactivated protein kinase (MAPK) signaling, CXCR4 and IL-3 signaling were all downregulated in I-MDSCs, compared to APCs (-4.0 < Z score > -2.0, Figure 4B)

Summary

Introduction

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of myeloid cells, halted at varying stages of maturation/differentiation and exert immunosuppressive activity on other immune cells [1, 2]. Myelopoiesis is disrupted in inflammationrelated cancers [5], such as colorectal cancer (CRC), leading to increased number of MDSCs in the circulation and tumor tissues [1, 2]. Increased level of MDSCs has been associated with poor prognosis and short survival periods in CRC patients [7,8,9]. MDSCs mediate immunosuppression by expressing co-inhibitory ligands, such as PD-L1, which induces T cell dysfunction upon the interaction with its receptor PD-1, and by expressing suppressive molecules, such as arginase-1 (ARG1), inducible nitric oxide synthase (iNOS), interleukin-10 (IL-10), and transforming growth factorb (TGF-b) [11, 12]. MDSCs promote tumorigenesis via other means, such as the induction of angiogenesis and tumor growth/metastasis, and activation of cancer-associated fibroblasts (CAFs) [12, 13]. Further insights into these mechanisms and pathways could result in the identification of potential therapeutic targets for cancer

Methods

Results

Conclusion