Abstract
BackgroundLong-term survival is still low for high-risk patients with soft tissue sarcoma treated with standard management options, including surgery, radiation, and chemotherapy. Immunotherapy is a promising new potential treatment paradigm. However, the application of immune checkpoint inhibitors for the treatment of patients with sarcoma did not yield promising results in a clinical trial. Therefore, there is a considerable need to identify factors that may lead to immune checkpoint inhibitor resistance.MethodsIn this study, we performed a bioinformatic analysis of The Cancer Genome Atlas (TCGA) to detect key long noncoding RNAs (lncRNAs) that were correlated with immune checkpoint inhibitory molecules in sarcoma. The expression levels of these lncRNAs and their correlation with patient prognosis were explored. The upstream long noncoding RNAs were also examined via 450K array data from the TCGA. The potential roles of these lncRNAs were further examined via KEGG and GO analysis using DAVID online software. Finally, the relationship between these lncRNAs and immune cell infiltration in tumors and their effect on immune checkpoint inhibitors were further explored.ResultsWe identified lncRNAs correlated with tumor cell immune evasion in sarcoma. The expression of these lncRNAs was upregulated and correlated with worse prognosis in sarcoma and other human cancer types. Moreover, low DNA methylation occupation of these lncRNA loci was detected. Negative correlations between DNA methylation and lncRNA expression were also found in sarcoma and other human cancer types. KEGG and GO analyses indicated that these lncRNAs correlated with immune evasion and negative regulation of the immune response in sarcoma. Finally, high expression of these lncRNAs correlated with more suppressive immune cell infiltration and reduced sensitivity to immune checkpoint inhibitors in sarcoma and other human cancer types.ConclusionOur results suggest that long noncoding RNAs confer immune checkpoint inhibitor resistance in human cancer. Further characterization of these lncRNAs may help to elucidate the mechanisms underlying immune checkpoint inhibitor resistance and uncover a novel therapeutic intervention point for immunotherapy.
Highlights
Sarcomas represent a cohort of rare and heterogeneous tumors with over 100 different histological subtypes occurring predominantly in the trunk, extremity, and retroperitoneal areas [1]
The gene expression profiles and clinical information of patients were obtained from The Cancer Genome Atlas (TCGA)
The results showed that the expression of nine immune checkpoint-related lncRNAs” (ICLs) was upregulated in different human cancer types (Figures 2 and 3)
Summary
Sarcomas represent a cohort of rare and heterogeneous tumors with over 100 different histological subtypes occurring predominantly in the trunk, extremity, and retroperitoneal areas [1]. These tumors exhibit a wide range of differing behaviors and underlying molecular pathologies [2,3,4]. In contrast to the genomic landscape of other tumor types, the genomic landscape of sarcomas is relatively simple, which offers the opportunity to identify driver events and translate these discoveries into clinically useful biomarkers [5, 6]. There is a considerable need to identify factors that may lead to immune checkpoint inhibitor resistance
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