Immune Landscape Refines the Classification of Colorectal Cancer With Heterogeneous Prognosis, Tumor Microenvironment and Distinct Sensitivity to Frontline Therapies.

Zaoqu Liu,Xiuxiu Yang,Dandan Fan,Yanxin Xu,Chen Chen,Zhenyu Ji,Qin Dang,Chaohua Si,Bo Shao,Xinwei Han,Xiaoke Wu,Yaxin Guo,Wenming Cui,Zhuang Chen,Zhenqiang Sun

doi:10.3389/fcell.2021.784199

Abstract

The immune microenvironment has profound impacts on the initiation and progression of colorectal cancer (CRC). Therefore, the goal of this article is to identify two robust immune subtypes in CRC, further provide novel insights for the underlying mechanisms and clinical management. In this study, two CRC immune subtypes were identified using the consensus clustering of immune-related gene expression profiles in the meta-GEO dataset (n = 1,198), and their reproducibility was further verified in the TCGA-CRC dataset (n = 638). Subsequently, we characterized the immune escape mechanisms, gene alterations, and clinical features of two immune subtypes. Cluster 1 (C1) was defined as the “immune cold subtype” with immune cell depletion and deficiency, while cluster 2 (C2) was designed as the “immune hot subtype”, with abundant immune cell infiltration and matrix activation. We also underlined the potential immune escape mechanisms: lack of MHC molecules and defective tumor antigen presentation capacity in C1, increased immunosuppressive molecules in C2. The prognosis and sensitivity to 5-FU, Cisplatin and immunotherapy differed between two subtypes. According to the two immune subtypes, we developed a prognosis associated risk score (PARS) with the accurate performance for predicting the prognosis. Additionally, two nomograms for overall survival (OS) and disease-free survival (DFS) were further constructed to facilitate clinical management. Overall, our research provides new references and insights for understanding and refining the CRC.

Highlights

Colorectal cancer (CRC) is a malignant tumor that originates from resident somatic stem cells and colorectal epithelial tissue (Perekatt et al, 2018)
To ensure the reproducibility and robustness of the immune subtypes derived from the Gene-Expression Omnibus (GEO) cohort, we further calculated the in-group proportion (IGP) statistic to validate the immune subtypes in the the Cancer Genome Atlas (TCGA)-CRC validation cohort
gene-set enrichment analysis (GSEA) analysis showed that cluster 2 (C2) was mainly enriched in matrix activation and immune activation related pathways (Figure 1E and Supplementary Figure S3E), while Cluster 1 (C1) was mainly enriched in cell proliferation related pathways (Figure 1F and Supplementary Figure S3F)

Summary

Introduction

Colorectal cancer (CRC) is a malignant tumor that originates from resident somatic stem cells and colorectal epithelial tissue (Perekatt et al, 2018). According to the anatomical location, CRC can be divided into colon cancer and rectal cancer. Adenocarcinoma is the most common pathological type of CRC, and very few are squamous cell carcinoma. The molecular classification improved the staging system and provides clues for mining CRC treatment targets (Calon et al, 2015). These molecular classification studies were primarily focused on tumor cell-intrinsic characteristics and did not consider the key roles of tumor immunity and tumor microenvironment in tumor progression

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