Perturbing DDR signaling enhances cytotoxic effects of local oncolytic virotherapy and modulates the immune environment in glioma.
Perturbing DDR signaling enhances cytotoxic effects of local oncolytic virotherapy and modulates the immune environment in glioma.
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DOI：
10.1016/j.omto.2022.07.009
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发表时间：
2022-09-15
期刊：
影响因子：
--
通讯作者：
Lawler, Sean E.
中科院分区：
文献类型：
--
作者：
Koch, Marilin S.;Zdioruk, Mykola;Nowicki, Michal O.;Griffith, Alec M.;Aguilar-Cordova, Estuardo;Aguilar, Laura K.;Guzik, Brian W.;Barone, Francesca;Tak, Paul Peter;Schregel, Katharina;Hoetker, Michael S.;Lederer, James A.;Chiocca, E. Antonio;Tabatabai, Ghazaleh;Lawler, Sean E.
CAN-2409是一种复制缺陷型腺病毒，编码单纯疱疹病毒（HSV）胸苷激酶（tk），目前正在临床试验中用于治疗胶质母细胞瘤。tk在转导的癌细胞中的表达导致前药更昔洛韦转化为毒性代谢物，引起DNA损伤，诱导免疫原性细胞死亡和免疫激活。我们假设CAN-2409与DNA损伤反应抑制剂组合可以放大肿瘤细胞死亡，从而改善反应。我们研究了ATR抑制剂AZD 6738与CAN-2409联合使用在胶质瘤细胞系中的细胞毒性、细胞因子和荧光激活细胞分选（FACS）试验中的体外作用，以及在原位同基因小鼠胶质瘤模型中的体内作用。通过飞行时间流式细胞术（CyTOF）分析肿瘤免疫浸润。在体外，我们观察到与单药治疗或对照相比，联合治疗后DNA损伤标志物γ H2 AX显著增加，PD-L1、促肿瘤细胞因子（白细胞介素-1 β [IL-1β]、IL-4）和配体NKG 2D表达降低。在体内，与CAN-2409（50%）和对照组相比，联合治疗后的长期存活率（66.7%）增加。在肿瘤再激发中，联合治疗后的长期免疫力未得到改善。我们的研究结果表明，ATR抑制可以通过增加DNA损伤来放大CAN-2409在胶质母细胞瘤中的功效，同时具有复杂的免疫学分支，从而避免进一步研究以确定最大化治疗益处的理想条件。CAN-2409是一种局部溶瘤疗法，正在进行胶质母细胞瘤的临床试验。它诱导DNA损伤和免疫细胞介导的肿瘤细胞杀伤。ATR抑制的DDR信号传导中断增强CAN-2409细胞毒性胶质瘤细胞杀伤能力并改变免疫应答。
CAN-2409 is a replication-deficient adenovirus encoding herpes simplex virus (HSV) thymidine kinase (tk) currently in clinical trials for treatment of glioblastoma. The expression of tk in transduced cancer cells results in conversion of the pro-drug ganciclovir into a toxic metabolite causing DNA damage, inducing immunogenic cell death and immune activation. We hypothesize that CAN-2409 combined with DNA-damage-response inhibitors could amplify tumor cell death, resulting in an improved response. We investigated the effects of ATR inhibitor AZD6738 in combination with CAN-2409 in vitro using cytotoxicity, cytokine, and fluorescence-activated cell sorting (FACS) assays in glioma cell lines and in vivo with an orthotopic syngeneic murine glioma model. Tumor immune infiltrates were analyzed by cytometry by time of flight (CyTOF). In vitro, we observed a significant increase in the DNA-damage marker γH2AX and decreased expression of PD-L1, pro-tumorigenic cytokines (interleukin-1β [IL-1β], IL-4), and ligand NKG2D after combination treatment compared with monotherapy or control. In vivo, long-term survival was increased after combination treatment (66.7%) compared with CAN-2409 (50%) and control. In a tumor re-challenge, long-term immunity after combination treatment was not improved. Our results suggest that ATR inhibition could amplify CAN-2409’s efficacy in glioblastoma through increased DNA damage while having complex immunological ramifications, warranting further studies to determine the ideal conditions for maximized therapeutic benefit. CAN-2409 is a local oncolytic therapy that is in clinical trials for glioblastoma. It induces DNA damage and immune-cell-mediated tumor cell killing. DDR signaling disruption with ATR inhibition enhances CAN-2409 cytotoxic glioma cell-killing abilities and modifies the immune response.
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