Integrated Analysis of the Transcriptome Profile Reveals the Potential Roles Played by Long Noncoding RNAs in Immunotherapy for Sarcoma

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.

Non-coding RNAs in drug and radiation resistance of bone and soft-tissue sarcoma: a systematic review

“…Only one study met our criteria for ncRNAs in sarcoma resistance to immunotherapy. One bioinformatic analysis reported that the overexpression of the lncRNAs ADAM6, C5orf58, CXCR2P1, FCGR2C, HCP5, HLA-H, NAPSB, NCF1B, and NCF1C reduced the sensitivity of sarcoma to ICIs ( Pang and Hao, 2021 ).…”

“…Recently, several lines of evidence have demonstrated that non-coding RNAs (ncRNAs), including miRNAs, long ncRNAs (lncRNAs), and circular RNAs (circRNAs), play vital roles in the resistance to a variety of therapies against bone and soft-tissue sarcomas, including chemotherapy reagents ( Fu et al, 2019 ), targeted therapy drugs ( Cao et al, 2016 ), immune checkpoint inhibitors (ICIs; Pang and Hao, 2021 ), and radiation ( He et al, 2020 ).…”

Application of Multi-Omics Approach in Sarcomas: A Tool for Studying Mechanism, Biomarkers, and Therapeutic Targets

“…Nine immune checkpoint-related lncRNAs (CD274, CD80, CD86, PDCD1 LG2, and LGALS9) were identified in a multi-omics research, the overexpression of which suggesting a worse outcome. Further investigation revealed their function of negative regulation in immune response, indicating a possible cause for the immunosuppressive environment in sarcomas, and may be a breakpoint in immunotherapy (50).…”

PINTology: A short history of the lncRNA LINC‐PINT in different diseases

“…Tumor heterogeneity is often cited as the main reason for such failures along with the unavailability of suitable diagnostic, therapeutic, and prognostic biomarkers. The lncRNAs studies have made substantial contributions to the understanding of underlying mechanisms of cancer development (Pang & Hao, 2021) but exploiting their potential as biomarkers and therapeutic targets is only just at the beginning. Notably, immune checkpoint inhibitor therapy has recently shown remarkable results in targeted cancer treatments.…”