Heterologous arenavirus vector prime-boost overrules self-tolerance for efficient tumor-specific CD8 T cell attack.
Heterologous arenavirus vector prime-boost overrules self-tolerance for efficient tumor-specific CD8 T cell attack.
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DOI：
10.1016/j.xcrm.2021.100209
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发表时间：
2021-03-16
期刊：
影响因子：
--
通讯作者：
Pinschewer DD
中科院分区：
文献类型：
--
作者：
Bonilla WV;Kirchhammer N;Marx AF;Kallert SM;Krzyzaniak MA;Lu M;Darbre S;Schmidt S;Raguz J;Berka U;Vincenti I;Pauzuolis M;Kerber R;Hoepner S;Günther S;Magnus C;Merkler D;Orlinger KK;Zippelius A;Pinschewer DD
治疗性疫苗接种方案诱导临床有效的肿瘤特异性CD8+T淋巴细胞(CTL)反应是一个尚未得到满足的医学需求。我们设计了两种远亲病毒，Pichinde病毒和淋巴细胞性脉络膜脑膜炎病毒，用于治疗性癌症疫苗接种。在小鼠中，这两种病毒的生命复制载体形式以异种Prime-Boost方案递送自身抗原，诱导高达50%的循环CD8T细胞池的肿瘤特异性CTL反应。这种CTL攻击消除了相当大比例动物中已建立的实体肿瘤，并伴随着对肿瘤再攻击的保护。CTL反应的大小是由警报驱动的，需要结合两种谱系上相距较远的Arena病毒。病媒中和抗体不会抑制同一病媒或密切相关病媒的加强免疫。相反，CTL免疫优势层级倾向于载体骨架靶向反应，而牺牲了自身反应性CTL。这些发现建立了一种基于ArenaVirus的免疫治疗方案，该方案允许重新洗牌免疫优势等级，并打破自我定向耐受，以有效控制肿瘤。基因工程阿雷诺病毒诱导强大的肿瘤自身特异性CD8 T细胞(CTL)应答远但亲缘关系不密切的阿雷诺病毒载体组合消除肿瘤载体主干靶向CTL应答与肿瘤自身反应性CTL竞争优化载体组合重组免疫优势打破自我耐受治疗肿瘤疫苗应打破自我耐受。评估工程阿雷诺病毒载体的组合，Bonilla等人。研究发现，距离较远的载体组合重新洗牌T细胞免疫优势等级，以打破自我耐受并消除已建立的实体肿瘤，而密切相关的载体干扰，因为抗载体CD8 T细胞而不是抗体的免疫优势。
Therapeutic vaccination regimens inducing clinically effective tumor-specific CD8+ T lymphocyte (CTL) responses are an unmet medical need. We engineer two distantly related arenaviruses, Pichinde virus and lymphocytic choriomeningitis virus, for therapeutic cancer vaccination. In mice, life-replicating vector formats of these two viruses delivering a self-antigen in a heterologous prime-boost regimen induce tumor-specific CTL responses up to 50% of the circulating CD8 T cell pool. This CTL attack eliminates established solid tumors in a significant proportion of animals, accompanied by protection against tumor rechallenge. The magnitude of CTL responses is alarmin driven and requires combining two genealogically distantly related arenaviruses. Vector-neutralizing antibodies do not inhibit booster immunizations by the same vector or by closely related vectors. Rather, CTL immunodominance hierarchies favor vector backbone-targeted responses at the expense of self-reactive CTLs. These findings establish an arenavirus-based immunotherapy regimen that allows reshuffling of immunodominance hierarchies and breaking self-directed tolerance for efficient tumor control. Engineered arenaviruses induce potent tumor self-specific CD8 T cell (CTL) response Combinations of distantly but not closely related arenavirus vectors eliminate tumors Vector backbone-targeted CTL responses compete against tumor self-reactive CTLs Optimized vector combinations reshuffle immunodominance to break self-tolerance Therapeutic tumor vaccination should break self-tolerance. Assessing combinations of engineered arenavirus vectors, Bonilla et al. find that distantly related vector combinations reshuffle T cell immunodominance hierarchies to break self-tolerance and eliminate established solid tumors, whereas closely related vectors interfere because of immunodominance of anti-vector CD8 T cells rather than antibodies.
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