Arming HSV-Based Oncolytic Viruses with the Ability to Redirect the Host's Innate Antiviral Immunity to Attack Tumor Cells.
Arming HSV-Based Oncolytic Viruses with the Ability to Redirect the Host's Innate Antiviral Immunity to Attack Tumor Cells.
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DOI：
10.1016/j.omto.2020.09.002
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发表时间：
2020-12-16
期刊：
影响因子：
--
通讯作者：
Zhang X
中科院分区：
文献类型：
--
作者：
Fu X;Tao L;Wu W;Zhang X
癌症免疫治疗的主要障碍之一是宿主的先天抗病毒防御机制。它们包括先天免疫细胞，如自然杀伤（NK）细胞和巨噬细胞，可以在数小时内招募到注射部位以清除引入的溶瘤病毒。在这里，我们报告了一种策略，重新定向这些浸润的先天免疫细胞攻击肿瘤细胞，而不是通过武装单纯疱疹病毒（HSV）衍生的溶瘤病毒与分泌的嵌合分子，可以使这些先天免疫细胞与肿瘤细胞，杀死后者。这些嵌合分子在其N末端具有针对肿瘤相关抗原（TAA）的定制结合部分，并且在其C末端具有结合免疫球蛋白（Ig）的蛋白L（PL）。PL与Ig的结合使Fc暴露于先天免疫细胞表面上的Fc受体，触发它们攻击接合的肿瘤细胞。在对溶瘤HSV具有有限容许性的鼠肿瘤模型中的体外和体内评价显示，用这些嵌合分子武装病毒显著增强杀伤作用和治疗活性。此外，我们的数据还表明，来自接合的先天免疫细胞和溶瘤病毒的组合杀伤作用导致比单独的病毒疗法更有效地刺激新抗原特异性抗肿瘤免疫。我们的数据表明，用这种策略武装溶瘤病毒代表了增强病毒疗法的溶瘤和免疫效果的独特和实用的方式。癌症免疫治疗面临的一个主要障碍是宿主的先天抗病毒防御机制。我们报告了一种策略，重新定向先天免疫细胞攻击肿瘤细胞。我们的数据表明，用这种策略武装溶瘤病毒代表了增强病毒疗法的溶瘤和免疫效果的独特方式。
One of the major hurdles for cancer immunotherapy is the host’s innate antiviral defense mechanisms. They include innate immune cells, such as natural killer (NK) cells and macrophages, which can be recruited within hours to the site of injection to clear the introduced oncolytic viruses. Here, we report a strategy to redirect these infiltrating innate immune cells to attack tumor cells instead by arming herpes simplex virus (HSV)-derived oncolytic viruses with secreted chimeric molecules that can engage these innate immune cells with tumor cells to kill the latter. These chimeric molecules have, at their N terminus, a custom-binding moiety for a tumor-associated antigen (TAA) and at their C terminus, protein L (PL) that binds to immunoglobulins (Igs). The binding of PL to Igs exposes the Fc to the Fc receptors on the surface of the innate immune cells, trigging them to attack the engaged tumor cells. In vitro and in vivo evaluation in a murine tumor model with limited permissiveness to oncolytic HSVs showed that arming the viruses with these chimeric molecules significantly boosts the killing effect and therapeutic activity. Moreover, our data also showed that the combined killing effect from the engaged innate immune cells and the oncolytic virus resulted in a more efficient stimulation of neoantigen-specific antitumor immunity than the virotherapy alone. Our data suggest that arming an oncolytic virus with this strategy represents a unique and pragmatic way of potentiating the oncolytic and immunotherapeutic effect of virotherapy. One major hurdle facing cancer immunotherapy is the host’s innate antiviral defense mechanisms. We report a strategy to redirect innate immune cells to attack tumor cells instead. Our data suggest that arming oncolytic viruses with this strategy represents a unique way of potentiating the oncolytic and immunotherapeutic effect of virotherapy.
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影响因子：
3.7
作者：
Abdul-Careem MF;Lee AJ;Pek EA;Gill N;Gillgrass AE;Chew MV;Reid S;Ashkar AA
通讯作者：
Ashkar AA
影响因子：
12.4
作者：
Fu, XP;Tao, L;Zhang, XL
通讯作者：
Zhang, XL
影响因子：
30.5
作者：
通讯作者：
--
DOI：
10.1186/bcr2866
发表时间：
2011-04-15
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
DeFazio-Eli L;Strommen K;Dao-Pick T;Parry G;Goodman L;Winslow J
通讯作者：
Winslow J
影响因子：
11.2
作者：
Fulci, Giulia;Dmitrieva, Nina;Chiocca, E. Antonio
通讯作者：
Chiocca, E. Antonio