Ghose Jayeeta, Dona Ada, Murtadha Mariam, Gunes Emine Gulsen, Caserta Enrico, Yoo Ji Young, Russell Luke, Jaime-Ramirez Alena Cristina, Barwick Benjamin G, Gupta Vikas A, Sanchez James F, Sborov Douglas W, Rosen Steven T, Krishnan Amrita, Boise Lawrence H, Kaur Balveen, Hofmeister Craig C, Pichiorri Flavia
Department of Radiation Oncology, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
Department of Hematology and Hematopoietic Cell Transplantation, Judy and Bernard Briskin Center for Multiple Myeloma Research, City of Hope, Monrovia, CA 91016, USA.
Mol Ther Oncolytics. 2021 Feb 18;20:519-531. doi: 10.1016/j.omto.2021.02.009. eCollection 2021 Mar 26.
Because most patients with multiple myeloma (MM) develop resistance to current regimens, novel approaches are needed. Genetically modified, replication-competent oncolytic viruses exhibit high tropism for tumor cells regardless of cancer stage and prior treatment. Receptors of oncolytic herpes simplex virus 1 (oHSV-1), NECTIN-1, and HVEM are expressed on MM cells, prompting us to investigate the use of oHSV-1 against MM. Using oHSV-1-expressing GFP, we found a dose-dependent increase in the GFP signal in MM cell lines and primary MM cells. Whereas NECTIN-1 expression is variable among MM cells, we discovered that HVEM is ubiquitously and highly expressed on all samples tested. Expression of HVEM was consistently higher on CD138/CD38 plasma cells than in non-plasma cells. HVEM blocking demonstrated the requirement of this receptor for infection. However, we observed that, although oHSV-1 could efficiently infect and kill all MM cell lines tested, no viral replication occurred. Instead, we identified that oHSV-1 induced MM cell apoptosis via caspase-3 cleavage. We further noted that oHSV-1 yielded a significant decrease in tumor volume in two mouse xenograft models. Therefore, oHSV-1 warrants exploration as a novel potentially effective treatment option in MM, and HVEM should be investigated as a possible therapeutic target.
由于大多数多发性骨髓瘤（MM）患者会对当前治疗方案产生耐药性，因此需要新的治疗方法。基因改造的、具有复制能力的溶瘤病毒对肿瘤细胞具有高度嗜性，无论癌症处于何种阶段以及之前接受过何种治疗。溶瘤单纯疱疹病毒1型（oHSV-1）的受体NECTIN-1和疱疹病毒侵入介质（HVEM）在MM细胞上表达，这促使我们研究oHSV-1对MM的治疗作用。利用表达绿色荧光蛋白（GFP）的oHSV-1，我们发现MM细胞系和原代MM细胞中GFP信号呈剂量依赖性增加。虽然NECTIN-1在MM细胞中的表达存在差异，但我们发现HVEM在所有测试样本中均普遍且高表达。HVEM在CD138/CD38浆细胞上的表达始终高于非浆细胞。阻断HVEM证明了该受体在感染中的必要性。然而，我们观察到，尽管oHSV-1能够有效感染并杀死所有测试的MM细胞系，但未发生病毒复制。相反，我们发现oHSV-1通过激活半胱天冬酶-3诱导MM细胞凋亡。我们进一步注意到，在两种小鼠异种移植模型中，oHSV-1使肿瘤体积显著减小。因此，oHSV-1作为MM一种新的潜在有效治疗选择值得探索，而HVEM应作为一个可能的治疗靶点进行研究。
