Wedekind Mary Frances, Miller Katherine E, Chen Chun-Yu, Wang Pin-Yi, Hutzen Brian J, Currier Mark A, Nartker Brooke, Roberts Ryan D, Boon Louis, Conner Joe, LaHaye Stephanie, Kelly Benjamin J, Gordon David, White Peter, Mardis Elaine R, Cripe Timothy P
Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, 700 Children's Drive Columbus, OH 43205, USA.
Division of Hematology/Oncology/Blood and Marrow Transplantation, Department of Pediatrics, The Ohio State University, Columbus, OH, USA.
iScience. 2021 Jun 19;24(7):102759. doi: 10.1016/j.isci.2021.102759. eCollection 2021 Jul 23.
Osteosarcoma remains one of the deadliest cancers in pediatrics and young adults. We administered two types of immunotherapies, oncolytic virotherapy and immune checkpoint inhibition, to two murine osteosarcoma models and observed divergent results. Mice bearing F420 showed no response, whereas those with K7M2 showed prolonged survival in response to combination therapy. K7M2 had higher expression of immune-related genes and higher baseline immune cell infiltrates, but there were no significant differences in tumor mutational burden or predicted MHC class I binding of nonsynonymous mutations. Instead, we found several mouse endogenous retrovirus sequences highly expressed in K7M2 compared with F420. T cell tetramer staining for one of them, gp70, was detected in mice with K7M2 but not F420, suggesting that endogenous retrovirus proteins are targets for the anti-tumor immune reaction. Given prior observations of endogenous retrovirus expression in human osteosarcomas, our findings may be translatable to human disease.
骨肉瘤仍然是儿科和年轻成年人中最致命的癌症之一。我们对两种小鼠骨肉瘤模型进行了两种免疫疗法，即溶瘤病毒疗法和免疫检查点抑制，并观察到了不同的结果。携带F420的小鼠没有反应，而携带K7M2的小鼠在联合治疗后存活时间延长。K7M2具有更高的免疫相关基因表达和更高的基线免疫细胞浸润，但肿瘤突变负担或非同义突变的预测MHC I类结合没有显著差异。相反，我们发现与F420相比，几种小鼠内源性逆转录病毒序列在K7M2中高度表达。对其中一种gp70进行的T细胞四聚体染色在携带K7M2的小鼠中检测到，而在F420小鼠中未检测到，这表明内源性逆转录病毒蛋白是抗肿瘤免疫反应的靶点。鉴于之前在人类骨肉瘤中观察到内源性逆转录病毒表达，我们的发现可能适用于人类疾病。
