Combination immune checkpoint blockade as an effective therapy for mesothelioma
Combination immune checkpoint blockade as an effective therapy for mesothelioma
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DOI：
10.1080/2162402x.2018.1494111
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发表时间：
2018-01-01
期刊：
影响因子：
7.2
通讯作者：
Fisher, Scott A.
中科院分区：
文献类型：
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作者：
Fear, Vanessa S.;Tilsed, Caitlin;Fisher, Scott A.
间皮瘤是一种由石棉引起的侵袭性癌症，预后极差，治疗选择有限。免疫检查点阻断(ICPB)已被证明是治疗黑色素瘤的有效方法，现在正被应用于其他癌症，包括间皮瘤。然而，ICPB的疗效以及哪些免疫检查点组合构成了间皮瘤的最佳治疗方案尚未完全阐明。在这里，我们使用我们特征良好的间皮瘤模型来研究不同ICBP治疗方法的有效性，以产生对间皮瘤的有效治疗。我们发现，相对于T效应亚群，肿瘤驻留调节性T细胞共表达高水平的CTLA-4、OX40和GITR，并且这些受体在很大一部分细胞上共表达。针对CTLA-4、OX40或GITR中的任何一个单独产生针对间皮瘤的有效反应。此外，CTLA-4和OX40的组合具有协同作用，肿瘤完全消退率从20%增加到80%。其他组合没有协同作用来提高治疗结果。最后，T细胞反应的早期模式预测了反应，从肿瘤和DLN中获得的T效应细胞的激活状态和ICP受体表达谱与免疫治疗的反应相关。综上所述，这些数据表明，联合ICPB可以协同作用，在动物模型中诱导对间皮瘤的强大、持久的免疫。
Mesothelioma is an aggressive asbestos induced cancer with extremely poor prognosis and limited treatment options. Immune checkpoint blockade (ICPB) has demonstrated effective therapy in melanoma and is now being applied to other cancers, including mesothelioma. However, the efficacy of ICPB and which immune checkpoint combinations constitute the best therapeutic option for mesothelioma have yet to be fully elucidated. Here, we used our well characterised mesothelioma tumour model to investigate the efficacy of different ICBP treatments to generate effective therapy for mesothelioma. We show that tumour resident regulatory T cell co-express high levels of CTLA-4, OX40 and GITR relative to T effector subsets and that these receptors are co-expressed on a large proportion of cells. Targeting any of CTLA-4, OX40 or GITR individually generated effective responses against mesothelioma. Furthermore, the combination of CTLA-4 and OX40 was synergistic, with an increase in complete tumour regressions from 20% to 80%. Other combinations did not synergise to enhance treatment outcomes. Finally, an early pattern in T cell response was predictive of response, with activation status and ICP receptor expression profile of T effector cells harvested from tumour and dLN correlating with response to immunotherapy. Taken together, these data demonstrate that combination ICPB can work synergistically to induce strong, durable immunity against mesothelioma in an animal model.