The Study of Sarcoma Microenvironment Heterogeneity Associated With Prognosis Based on an Immunogenomic Landscape Analysis

Jin Deng,Wei Kong,Weiming Zeng,Xiaoyang Mou,Yuhu Shi

doi:10.3389/fbioe.2020.01003

Abstract

Microenvironment-driven tumor heterogeneity causes the limitation of immunotherapy of sarcomas. Nonetheless, systematical studies of various molecular levels can enhance the understanding of tumor microenvironment (TME) related to prognosis and provide novel insights of precision immunotherapy. Three prognostic-related TME phenotypes were identified by consensus clustering of the relative infiltration of 22 immune cells from 869 samples of sarcomas. Additionally, integrative immunogenomic analysis is applied to explore the characteristics of different TME groups. The results revealed that most of the immune cell infiltration is higher in the better prognostic group, which are more affected by lower DNA methylation levels and fewer copy number variations in the worse prognostic group. The signaling pathway crosstalk analysis suggested that the changes in the TME will cause considerable variation in the flow of information between pathways, especially when the degree of relative infiltration of immune cells is low, patient’s endocrine system may also be significantly affected. Also, the endogenous competitive network analysis indicated that several differentially expressed long non-coding RNAs (lncRNAs) associated with the prognosis or tumor recurrence of sarcoma patients affected the regulatory relationship between miRNAs and different genes when the sarcoma microenvironment changes. In summary, the significant relationship between genetic alterations and prognostic-related TME characteristics in sarcomas were determined in this study. These findings may provide new clues for the treatment of sarcomas.

Highlights

Sarcoma refers to malignant tumors caused by problems in human muscle and connective tissue, the characters of which are mainly rapid disease progression, short duration, and high-frequency metastasis (Daw et al, 2015; Giuliano et al, 2016; Steele and Pillay, 2019; Deng et al, 2020b)
It is the first time to use gene expression data of over 800 sarcomas samples to identify the subtypes of tumor microenvironment (TME) and to analyze the difference from multiple dimensional molecular data
The infiltration degree of 22 kinds of immune cells in each sample was estimated, which was applied to divide all samples into three TME groups

Summary

Introduction

Sarcoma refers to malignant tumors caused by problems in human muscle and connective tissue, the characters of which are mainly rapid disease progression, short duration, and high-frequency metastasis (Daw et al, 2015; Giuliano et al, 2016; Steele and Pillay, 2019; Deng et al, 2020b). The Cancer Genome Atlas (TCGA) Research Network has comprehensively integrated genomic characterization of adult soft tissue sarcomas, and previous studies have used some sarcoma gene expression data to infer the degree of infiltration (The Cancer Genome Atlas Research Network,, 2017; Huang et al, 2019; Stahl et al, 2019). These studies have only identified the associated characteristic genes after inferring the relative infiltration abundance of immune cells based on the level of single gene expression data, without identifying microenvironment phenotypes from the aspect of multiple dimensional data. There is a tremendous need to comprehensively explore the TME phenotypes of sarcomas from a multi-dimensional perspective

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Results

Conclusion