Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Nat Commun. 2020 Feb 21;11(1):1008. doi: 10.1038/s41467-020-14646-w.
Limited clinical activity has been seen in osteosarcoma (OS) patients treated with immune checkpoint inhibitors (ICI). To gain insights into the immunogenic potential of these tumors, we conducted whole genome, RNA, and T-cell receptor sequencing, immunohistochemistry and reverse phase protein array profiling (RPPA) on OS specimens from 48 pediatric and adult patients with primary, relapsed, and metastatic OS. Median immune infiltrate level was lower than in other tumor types where ICI are effective, with concomitant low T-cell receptor clonalities. Neoantigen expression in OS was lacking and significantly associated with high levels of nonsense-mediated decay (NMD). Samples with low immune infiltrate had higher number of deleted genes while those with high immune infiltrate expressed higher levels of adaptive resistance pathways. PARP2 expression levels were significantly negatively associated with the immune infiltrate. Together, these data reveal multiple immunosuppressive features of OS and suggest immunotherapeutic opportunities in OS patients.
在接受免疫检查点抑制剂（ICI）治疗的骨肉瘤（OS）患者中，观察到有限的临床活性。为了深入了解这些肿瘤的免疫原性潜力，我们对来自 48 名患有原发性、复发性和转移性 OS 的儿科和成年患者的 OS 标本进行了全基因组、RNA 和 T 细胞受体测序、免疫组织化学和反相蛋白阵列分析（RPPA）。中位免疫浸润水平低于其他 ICI 有效的肿瘤类型，同时 T 细胞受体克隆性较低。OS 中的新抗原表达缺失，并与高水平的无义介导的衰变（NMD）显著相关。免疫浸润低的样本中缺失的基因数量更多，而免疫浸润高的样本中适应性耐药途径的表达水平更高。PARP2 表达水平与免疫浸润呈显著负相关。综上所述，这些数据揭示了 OS 的多种免疫抑制特征，并为 OS 患者的免疫治疗提供了机会。
