Pang Boran, Hao Yongqiang
Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Clinical and Translational Research Center for 3D Printing Technology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Front Oncol. 2021 Jun 11;11:690486. doi: 10.3389/fonc.2021.690486. eCollection 2021.
Long-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.
In 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 450K array data from the TCGA. The potential roles of these lncRNAs were further examined 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.
We 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.
Our 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.
对于采用包括手术、放疗和化疗在内的标准治疗方案的软组织肉瘤高危患者，其长期生存率仍然较低。免疫疗法是一种有前景的新潜在治疗模式。然而，免疫检查点抑制剂在肉瘤患者治疗中的应用在一项临床试验中并未产生理想结果。因此，迫切需要确定可能导致免疫检查点抑制剂耐药的因素。
在本研究中，我们对癌症基因组图谱（TCGA）进行了生物信息学分析，以检测与肉瘤中免疫检查点抑制分子相关的关键长链非编码RNA（lncRNA）。探讨了这些lncRNA的表达水平及其与患者预后的相关性。还利用TCGA的450K阵列数据检查了上游长链非编码RNA。使用DAVID在线软件通过KEGG和GO分析进一步研究了这些lncRNA的潜在作用。最后，进一步探讨了这些lncRNA与肿瘤中免疫细胞浸润的关系及其对免疫检查点抑制剂的影响。
我们鉴定出了与肉瘤中肿瘤细胞免疫逃逸相关的lncRNA。这些lncRNA的表达上调，且与肉瘤及其他人类癌症类型中更差的预后相关。此外，检测到这些lncRNA基因座的低DNA甲基化占有率。在肉瘤及其他人类癌症类型中也发现了DNA甲基化与lncRNA表达之间的负相关。KEGG和GO分析表明，这些lncRNA与肉瘤中的免疫逃逸和免疫反应的负调控相关。最后，在肉瘤及其他人类癌症类型中，这些lncRNA的高表达与更多抑制性免疫细胞浸润以及对免疫检查点抑制剂的敏感性降低相关。
我们的结果表明，长链非编码RNA赋予人类癌症免疫检查点抑制剂耐药性。对这些lncRNA的进一步表征可能有助于阐明免疫检查点抑制剂耐药的潜在机制，并揭示免疫治疗的新治疗干预点。
