BiTEs expressed by an oncolytic herpes simplex virus type 2 can transform heterologous T cells into uniform tumor killer cells.
BiTEs expressed by an oncolytic herpes simplex virus type 2 can transform heterologous T cells into uniform tumor killer cells.
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DOI：
10.1089/hum.2021.277
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发表时间：
2022-03
影响因子：
4.2
通讯作者：
Jing Jin;Runyang Wang;Junhan Yang;Han Hu;Di Wang;Linkang Cai;Zhizheng Fang;S. Dong;Sheng Hu
中科院分区：
文献类型：
--
作者：
Jing Jin;Runyang Wang;Junhan Yang;Han Hu;Di Wang;Linkang Cai;Zhizheng Fang;S. Dong;Sheng Hu
BiTEs (bispecific T-cell engagers ) armed oncolytic viruses are effective in regulating tumor micro-environment. However, oHSV2 (oncolytic herpes simplex virus type 2) expressing immune checkpoints targeting BiTEs are not reported. Here, we generated oHSV2 armed BiTEs and established pharmacodynamic evaluation models, which suggested that our oHSV2-BiTEs have an improved oncolytic potency in vitro and in vivo. The oHSV2 viruses armed with BiTEs targeting PD-L1 or CD19 (oHSV2-BiTEs-PD-L1 or oHSV2-mBiTEs-CD19) were constructed, besides inducing oncolysis in virus infected tumor cells, the modified oncolytic virus oHSV2-BiTEs-PD-L1 can also activate peripheral blood mononuclear cells (PBMCs) by releasing BiTEs-PD-L1 and thereby induce PBMCs-mediated killing of PD-L1 positive tumor cells, regardless of PD-L1 expression level. The expressed BiTEs-PD-L1 can up-regulate the activation markers of T cells in PBMCs and induce different cytokine secretion. The activation of T cells and the enrichment of related immune regulatory pathways are further confirmed by proteomics. It is also demonstrated that the oncolytic viruses or PBMCs could up-regulate PD-L1 expression on the surface of tumor cells through transforming "cold tumors" with low PD-L1 expression into "hot tumors" with high PD-L1 expression, which can facilitate the targeting of BiTEs and enhance the effect of oncolysis. oHSV2-BiTEs-PD-L1 or oHSV2-mBiTEs-CD19 showed an enhanced oncolytic effect in vitro and in vivo compared to backbone virus oHSV2-GFP. Our results showed that the newly designed oHSV2-BiTEs had enhanced therapeutic effects against solid tumors and provided a new option of immunotherapy.
