Smac mimetics synergize with immune checkpoint inhibitors to promote tumour immunity against glioblastoma.
Smac mimetics synergize with immune checkpoint inhibitors to promote tumour immunity against glioblastoma.
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DOI：
10.1038/ncomms14278
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发表时间：
2017-02-15
影响因子：
16.6
通讯作者：
Korneluk RG
中科院分区：
文献类型：
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作者：
Beug ST;Beauregard CE;Healy C;Sanda T;St-Jean M;Chabot J;Walker DE;Mohan A;Earl N;Lun X;Senger DL;Robbins SM;Staeheli P;Forsyth PA;Alain T;LaCasse EC;Korneluk RG
小分子细胞凋亡抑制拮抗剂，称为Smac模拟化合物(SMCs)，使肿瘤对肿瘤坏死因子-α诱导的杀伤敏感，同时阻断肿瘤坏死因子-α生长促进活性。SMC还调节免疫细胞内的几种免疫调节特性。我们报道，SMCs与天然免疫刺激剂和免疫检查点抑制物生物制剂协同作用，在单一药物治疗无效的小鼠胶质母细胞瘤模型中产生持久的治愈。这些治疗药物之间的活性互补依赖于细胞毒性T细胞活性，并与免疫抑制T细胞的减少有关。值得注意的是，协同作用依赖于I型干扰素和肿瘤坏死因子-α信号。此外，我们的结果暗示了产生肿瘤坏死因子-α的细胞毒性T细胞在免疫检查点抑制剂与SMC结合时在介导抗肿瘤作用中的重要作用。总体而言，这种组合方法在临床应用上可能是非常有效的，因为它允许在免疫细胞介导的癌细胞死亡中建立合作和互补的机制。Smac模拟物使癌细胞对外源性细胞死亡途径敏感，并刺激抗肿瘤免疫。在这项研究中，作者表明，Smac模拟物可以与免疫检查点抑制剂协同作用，以细胞毒性CD8+T细胞和肿瘤坏死因子α依赖的方式控制小鼠癌症模型中的肿瘤生长，包括侵袭性中枢神经系统肿瘤。
Small-molecule inhibitor of apoptosis (IAP) antagonists, called Smac mimetic compounds (SMCs), sensitize tumours to TNF-α-induced killing while simultaneously blocking TNF-α growth-promoting activities. SMCs also regulate several immunomodulatory properties within immune cells. We report that SMCs synergize with innate immune stimulants and immune checkpoint inhibitor biologics to produce durable cures in mouse models of glioblastoma in which single agent therapy is ineffective. The complementation of activities between these classes of therapeutics is dependent on cytotoxic T-cell activity and is associated with a reduction in immunosuppressive T-cells. Notably, the synergistic effect is dependent on type I IFN and TNF-α signalling. Furthermore, our results implicate an important role for TNF-α-producing cytotoxic T-cells in mediating the anti-cancer effects of immune checkpoint inhibitors when combined with SMCs. Overall, this combinatorial approach could be highly effective in clinical application as it allows for cooperative and complimentary mechanisms in the immune cell-mediated death of cancer cells. Smac mimetics sensitize cancer cells to the extrinsic cell death pathway and stimulate anti-tumour immunity. In this study, the authors show that Smac mimetics can synergize with immune checkpoint inhibitors to control tumour growth in mouse cancer models, including aggressive CNS tumours, in a cytotoxic CD8+ T-cell- and TNFα-dependent manner.