背景:免疫检查点阻断在骨肉瘤(OS)中仍然不清楚。我们旨在探讨可溶性免疫检查点(ICK)相关蛋白在OS中的临床意义。
方法:我们分析了14种可溶性ICK相关蛋白(BTLA,GITR,HVEM,IDO,76例OS患者和匹配对照血浆中的LAG-3,PD-1,PD-L1,PD-L2,TIM-3,CD28,CD80,CD137,CD27和CTLA-4)。我们使用非条件多变量逻辑回归评估了生物标志物与OS风险之间的关联。利用多元Cox模型建立了OS的预测模型。从鉴定的生物标志物建立免疫亚型。分析了来自GEO的转录数据以阐明潜在的机制。
结果:我们发现sTIM3、sCD137、sIDO、sCTLA4与OS风险显著相关(均p<0.05)。sBTLA,sPDL2和sCD27与肺转移风险显著相关,而sBTLA和sTIM3与疾病进展的风险相关。我们还建立了基于sBTLA的免疫亚型,sPD1、sTIM3和sPDL2。sICK-type2亚型患者的无进展生存期(PFS)和肺无转移生存期(LMFS)明显低于sICK-type1亚型患者(log-rankp=2.8×10-2,1.7×10-2,分别)。有趣的是,我们发现,相应ICK基因表达亚型中LMFS和PFS的趋势与血液中的结果相反(log-rankp分别为2.6×10-4、9.5×10-4)。
结论:四种可溶性ICK相关蛋白与OS患者的生存相关。可溶性ICK相关蛋白可能是OS患者预后和免疫治疗的有希望的生物标志物。尽管有必要进行更多的研究。
BACKGROUND: The immune checkpoint blockade remains obscure in osteosarcoma (OS). We aim to explore the clinical significance of soluble immune checkpoint (ICK)-related proteins in OS.
METHODS: We profiled 14 soluble ICK-related proteins (BTLA, GITR, HVEM, IDO, LAG-3, PD-1, PD-L1, PD-L2, TIM-3, CD28, CD80, CD137, CD27, and CTLA-4) in the plasma of 76 OS patients and matched controls. We evaluated the associations between the biomarkers and the risk of OS using unconditional multivariate logistic regression. The multivariate Cox model was utilized to develop the prediction model of OS. Immune subtypes were established from the identified biomarkers. Transcriptional data from GEO were analyzed to elucidate potential mechanisms.
RESULTS: We found that sTIM3, sCD137, sIDO, and sCTLA4 were significantly correlated with OS risk (all p < 0.05). sBTLA, sPDL2, and sCD27 were significantly associated with the risk of lung metastasis, whereas sBTLA and sTIM3 were associated with the risk of disease progression. We also established an immune
subtype based on sBTLA, sPD1, sTIM3, and sPDL2. Patients in the sICK-type2
subtype had significantly decreased progression-free survival (PFS) and lung metastasis-free survival (LMFS) than those in the sICK-type1
subtype (log-rank p = 2.8 × 10-2, 1.7 × 10-2, respectively). Interestingly, we found that the trend of LMFS and PFS in the subtypes of corresponding ICK genes\' expression was opposite to the results in the blood (log-rank p = 2.6 × 10-4, 9.5 × 10-4, respectively).
CONCLUSIONS: Four soluble ICK-related proteins were associated with the survival of OS patients. Soluble ICK-related proteins could be promising biomarkers for the outcomes and immunotherapy of OS patients, though more research is warranted.