Antitumor cytotoxic T lymphocytes (CTLs) are essential for immune surveillance, yet the blockade of eliciting such CTLs during oncolytic virotherapy remains incompletely understood. Here, we show that oncolysis of mesothelioma by modified vaccinia Tiantan (MVTT) induces damage-associated molecular patterns exposure. Although MVTT leads to regression of established mesothelioma dose-dependently, antitumor CTLs are rarely induced. Mechanistically, MVTT virotherapy generates C-X-C chemokines that recruit CXCR2-expressing polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) into tumor microenvironment, where they suppress dendritic cells (DCs) by producing IL-10 and halt CTL responses. During the virotherapy, however, depletion of PMN-MDSCs but not of monocytic (M)-MDSCs results in the induction of potent antitumor CTLs that not only eradicate established mesothelioma but also prevent the second tumor challenge. Our findings suggest that vaccinia virotherapy may combine strategies that prevent the chemotactic recruitment of PMN-MDSCs, block their suppression on DCs or deplete PMN-MDSCs in order to induce potent CTLs for tumor eradication.

中文翻译：

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病毒疗法诱导的间皮瘤PMN-MDSC浸润可通过IL-10介导的树突状细胞抑制作用来阻断抗肿瘤CTL。

抗肿瘤细胞毒性T淋巴细胞（CTL）对于免疫监视至关重要，但是对溶瘤病毒治疗期间引发此类CTL的阻滞作用尚不完全清楚。在这里，我们表明间皮瘤由改良牛痘天坛（MVTT）的溶瘤诱导损伤相关的分子模式暴露。尽管MVTT剂量依赖性地导致已建立的间皮瘤消退，但很少诱导出抗肿瘤CTL。从机理上讲，MVTT病毒疗法产生CXC趋化因子，将表达CXCR2的多形核髓样抑制细胞（PMN-MDSC）募集到肿瘤微环境中，在那里它们通过产生IL-10和阻止CTL反应来抑制树突状细胞（DC）。然而，在病毒疗法期间，PMN-MDSCs的耗竭而不是单核细胞（M）-MDSCs的耗竭导致诱导有效的抗肿瘤CTL，这些CTL不仅根除已建立的间皮瘤，还可以防止第二次肿瘤攻击。我们的发现表明，牛痘病毒疗法可能会结合以下策略：预防PMN-MDSC的趋化性募集，阻止其对DC的抑制或耗尽PMN-MDSC，以诱导有效的CTL消灭肿瘤。