Gastric Cancer Tumor Microenvironment Characterization Reveals Stromal-Related Gene Signatures Associated With Macrophage Infiltration

Abstract

The tumor microenvironment (TME) has attracted attention owing to its essential role in tumor initiation, progression, and metastasis. With the emergence of immunotherapies for various cancers, and their high efficacy, an understanding of the TME in gastric cancer (GC) is critical. The aim of this study was to investigate the effect of various components within the GC TME, and to identify mechanisms that exhibit potential as therapeutic targets. The ESTIMATE algorithm was used to quantify immune and stromal components in GC samples, whose clinicopathological significance and relationship with predicted outcomes were explored. Low tumor mutational burden and high M2 macrophage infiltration, which are considered immune suppressive characteristics and may be responsible for unfavorable prognoses in GC, were observed in the high stromal group (HR = 1.585; 95% CI, 1.112-2.259; P = 0.009). Furthermore, weighted correlation network, differential expression, and univariate Cox analyses were used, along with machine learning methods (LASSO and SVM-RFE), to reveal genome-wide immune phenotypic correlations. Eight stromal-relevant genes cluster (FSTL1, RAB31, FBN1, ANTXR1, LRRC32, CTSK, COL5A2, and ENG) were identified as adverse prognostic factors in GC. Finally, using a combination of TIMER database and single-sample gene set enrichment analyses, we found that the identified genes potentially contribute to macrophage recruitment and polarization of tumor-associated macrophages. These findings provide a different perspective into the immune microenvironment and indicate potential prognostic and therapeutic targets for GC immunotherapies.

Landscape Of M6a RNA Methylation Regulators and Tumor Microenvironment Cell-Infiltration Characterization In Gastroesophageal Adenocarcinomas

“…Several studied had reported that COL5A2 might function as crucial role in the initiation and progression of tumor by using bioinformatics technologies [28,29]. More importantly, COL5A2, was correlated with stromal scores in GC, promoted the recruitment of circulating monocytes into the TME and facilitated their differentiation into tumor-associated macrophages [30]. Similarly, in our research, we found that COL4A1 and COL5A2 were signi cantly related to prognosis of GEA patients and regulate TME in ltration characteristics.…”

A Non-canonical Wnt Signature Correlates With Lower Survival in Gastric Cancer

“…The presence of tumor-infiltrating immune cells (TIICs) in the tumor microenvironment is usually associated with poor prognosis ( Fridman et al, 2012 ) and has been characterized recently in GC ( Li et al, 2019 ; Wang et al, 2020 ; Wei et al, 2020 ; Wu et al, 2020 ). To determine if the non-canonical Wnt signatures are correlated with immune cell infiltration, the correlation between the two gene signatures and markers of specific immune cell types was assessed using GEPIA (“signature-to-signature” comparison).…”

“…Second, the “Gene” module from TIMER (version 1.0) was employed to assess immune cell infiltration. Immune ( Wei et al, 2020 ) and epithelial/mesenchymal ( Xue et al, 2020 ) gene signatures were used to assess the correlation between non-canonical gene signatures and immune infiltration or EMT, respectively. The markers employed are listed in Supplementary Table 1 .…”

Screening Potential Prognostic Factors for gastric carcinoma and Indicators for Tumor Microenvironment Remodeling in Female and Male patients Based on TCGA Data Mining

“…Xiaolong Wu reported that GC patients with high levels of T cell in ammation were more likely to bene t from adjuvant chemotherapy [17]. In contrast, it was reported that stromal-relevant genes were identi ed as adverse prognostic factors in GC [18]. Interestingly, our study found that a high StromalScore was positively correlated with the survival rate of both female and male patients, while a high ImmuneScore was negatively correlated with the survival rate in female samples and positively correlated with male samples.…”