ΔPK oncolytic activity includes modulation of the tumour cell milieu
ΔPK oncolytic activity includes modulation of the tumour cell milieu
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DOI：
10.1099/jgv.0.000353
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发表时间：
2016-02-01
影响因子：
3.8
通讯作者：
Aurelian, Laure
中科院分区：
文献类型：
--
作者：
Bollino, Dominique;Colunga, Aric;Aurelian, Laure
溶瘤病毒疗法是一种独特的癌症治疗方法，包括通过病毒复制和程序性细胞死亡（PCD）途径裂解肿瘤细胞。尽管如此，临床疗效相对温和，可能与免疫抑制肿瘤环境有关。我们的研究使用基于单纯疱疹病毒2型（HSV-2）的溶瘤病毒Delta PK，该病毒已记录了与病毒复制、PCD和癌症干细胞溶解相关的抗肿瘤活性。它们旨在检查Delta PK介导的溶瘤作用是否包括通过改变黑色素瘤细胞直接分泌的细胞因子的平衡来逆转免疫抑制性肿瘤微环境的能力，并确定其机制。在这里，我们表明，黑色素瘤细胞分泌的免疫抑制细胞因子IL-10，并通过病毒复制和c-Jun N-末端激酶/c-Jun激活Delta PK抑制分泌。δ PK诱导的IL-10抑制上调了MHC I类链相关蛋白A的表面表达，该蛋白A是NK细胞和细胞毒性T细胞上表达的活化NKG 2D受体的配体。同时，DPK还通过自噬介导的Toll样受体2途径活化和细胞凋亡上调炎性细胞因子TNF-α、粒细胞巨噬细胞集落刺激因子和IL-1 β的分泌，并抑制负性免疫检查点调节因子细胞毒性T淋巴细胞抗原4的表达。这些过程的药理学抑制显著降低了Delta PK的溶瘤活性。
Oncolytic virotherapy is a unique cancer therapeutic that encompasses tumour cell lysis through both virus replication and programmed cell death (PCD) pathways. Nonetheless, clinical efficacy is relatively modest, likely related to the immunosuppressive tumour milieu. Our studies use the herpes simplex virus type 2 (HSV-2)-based oncolytic virus Delta PK that has documented anti-tumour activity associated with virus replication, PCD and cancer stem cell lysis. They are designed to examine whether Delta PK-mediated oncolysis includes the ability to reverse the immunosuppressive tumour microenvironment by altering the balance of cytokines directly secreted by the melanoma cells and to define its mechanism. Here, we show that melanoma cells secreted the immunosuppressive cytokine IL-10, and that secretion was inhibited by Delta PK through virus replication and c-Jun N-terminal kinase/c-Jun activation. Delta PK-induced IL-10 inhibition upregulated surface expression of MHC class I chain-related protein A, the ligand for the activating NKG2D receptor expressed on NK- and cytotoxic T-cells. Concomitantly, DPK also upregulated the secretion of inflammatory cytokines TNF-alpha, granulocyte macrophage colony-stimulating factor and IL-1 beta through autophagy-mediated activation of Toll-like receptor 2 pathways and pyroptosis, and it inhibited the expression of the negative immune checkpoint regulator cytotoxic T-lymphocyte antigen 4. Pharmacologic inhibition of these processes significantly reduces the oncolytic activity of Delta PK.