Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63010, USA.
Institute of Informatics, Washington University School of Medicine, St. Louis, MO 63110, USA.
Pathol Res Pract. 2019 Jun;215(6):152395. doi: 10.1016/j.prp.2019.03.023. Epub 2019 Apr 18.
Malignant rhabdoid tumor (MRT) is a rare, aggressive pediatric tumor of nuclear lineage. It is mainly characterized by germline or somatic SMARCB1 (INI1) driver mutations. To characterize the potential for immunotherapy in untreated and treated MRT, current study investigated tumor mutational burden (TMB) and other biomarkers in MRT.
Normal-tumor paired whole exome sequencing (WES) and/or immunohistochemistry (IHC) of DNA mismatch repair (MMR) proteins, PD-L1, PD-1 and CD8 were performed in 16 cases, some with both primary and relapsed tumor.
Five cases subjected to WES demonstrated germline SMARCB1 (INI1) mutations. TMB was 0.7-1.07/Mb in 4 of the 5 primary untreated tumors, and 33.81/Mb in one case with pathogenic MMR, POLD, and POLE mutations. Ten cases tested for MMR status by IHC showed retained nuclear expression of the proteins. Eight of the 16 cases (8/16, 50%) showed membranous expression of PD-L1 in 10-70% of tumor cells (tumor proportion score, TPS). Nine cases (9/16, 56.3%) showed high (>2/HPF) tumor infiltrating lymphocytes with PD-1 staining ranging 10-60%, correlating with tumor PD-L1 staining (p < 0.0001). Between post-treatment metastatic tumors and the pre-treatment primary tumors, TMB was similar while PD-L1 TPS was similar or lower.
MRT has a low TMB. Nonetheless, because a subset of MRT cases have a PD-L1 TPS greater than the cutoff for checkpoint therapy in other malignancies, the utility of immune checkpoint inhibitors should be studied in this patient population.
恶性横纹肌样瘤（MRT）是一种罕见的、具有侵袭性的儿童神经源性肿瘤。它主要表现为胚系或体细胞 SMARCB1（INI1）驱动突变。为了研究未治疗和治疗后的 MRT 免疫治疗的潜力，本研究检测了 MRT 中的肿瘤突变负担（TMB）和其他生物标志物。
对 16 例病例进行了正常-肿瘤配对的全外显子测序（WES）和/或 DNA 错配修复（MMR）蛋白的免疫组化（IHC）检测、PD-L1、PD-1 和 CD8，其中一些病例同时进行了原发肿瘤和复发肿瘤的检测。
5 例进行 WES 的病例显示存在胚系 SMARCB1（INI1）突变。4 例未经治疗的原发性肿瘤的 TMB 为 0.7-1.07/Mb，1 例存在致病性 MMR、POLD 和 POLE 突变的肿瘤的 TMB 为 33.81/Mb。10 例通过 IHC 检测 MMR 状态的病例显示出核蛋白的保留表达。16 例病例中的 8 例（8/16，50%）在 10-70%的肿瘤细胞中（肿瘤比例评分，TPS）显示 PD-L1 的膜表达。9 例（9/16，56.3%）显示高（>2/HPF）肿瘤浸润淋巴细胞，PD-1 染色范围为 10-60%，与肿瘤 PD-L1 染色相关（p<0.0001）。在治疗后转移瘤和治疗前的原发性肿瘤之间，TMB 相似，而 PD-L1 TPS 相似或更低。
MRT 的 TMB 较低。尽管如此，由于一部分 MRT 病例的 PD-L1 TPS 大于其他恶性肿瘤中免疫检查点治疗的截止值，因此应该在该患者人群中研究免疫检查点抑制剂的应用。
