PD-L1 and IAPs co-operate to protect tumors from cytotoxic lymphocyte-derived TNF
PD-L1 and IAPs co-operate to protect tumors from cytotoxic lymphocyte-derived TNF
复制标题
DOI：
10.1038/cdd.2017.94
复制
发表时间：
2017-10-01
影响因子：
12.4
通讯作者：
Oliaro, Jane
中科院分区：
文献类型：
--
作者：
Kearney, Conor J.;Lalaoui, Najoua;Oliaro, Jane
Smac模拟物正在成为有前途的抗癌剂，并正在评估各种恶性肿瘤的临床试验。Smac模拟物可以诱导肿瘤细胞产生TNF，同时使它们对TNF诱导的凋亡敏感。然而，来自其他细胞来源的TNF，如肿瘤内的细胞毒性淋巴细胞（CL），也可能有助于SM的抗肿瘤活性。在这里，我们表明，在SM，birinapant存在下，CD 8（+）T细胞和NK细胞有效地杀死肿瘤细胞。增强的CL杀伤发生在肿瘤抗原识别或NK激活受体连接后通过TNF分泌。重要的是，CL介导的肿瘤细胞杀伤的穿孔素/颗粒酶途径对于birinapant的功效是无效的，强调了TNF介导的细胞凋亡途径的重要性。延时显微镜显示，birinapant使肿瘤细胞对作为旁观者的凋亡和在免疫突触内递送至肿瘤细胞的膜结合TNF敏感。此外，肿瘤细胞上的PD-L1表达抑制了CD 8（+）T细胞抗原驱动的TNF产生，这可以通过PD-1阻断来拮抗。重要的是，当与birinapant组合时，PD-1阻断后产生的TNF水平升高进一步增强了肿瘤细胞杀伤。IAP拮抗和PD-1阻断的组合抗肿瘤活性独立于穿孔素介导的肿瘤细胞死亡而发生。综上所述，我们鉴定了CL衍生的TNF作为birinapant介导的抗肿瘤免疫的有效效应物，以及通过免疫检查点的共抑制进行联合治疗的机会。
Smac-mimetics are emerging as promising anti-cancer agents and are being evaluated in clinical trials for a variety of malignancies. Smac-mimetics can induce TNF production from a subset of tumor cells and simultaneously sensitize them to TNF-induced apoptosis. However, TNF derived from other cellular sources, such as cytotoxic lymphocytes (CLs) within the tumor, may also contribute to the anti-tumor activity of SMs. Here, we show that CD8(+) T cells and NK cells potently kill tumor cells in the presence of the SM, birinapant. Enhanced CL killing occurred through TNF secretion upon tumor antigen recognition or NK-activating receptor ligation. Importantly, the perforin/granzyme route to CL-mediated tumor cell killing was dispensable for the efficacy of birinapant, emphasizing the importance of the TNF-mediated apoptosis pathway. Time-lapse microscopy revealed that birinapant sensitized tumor cells to apoptosis as bystanders and to membrane-bound TNF delivered to tumor cells within the immunological synapse. Furthermore, PD-L1 expression on tumor cells suppressed antigen-driven TNF production by CD8(+) T cells, which could be antagonized through PD-1 blockade. Importantly, the elevated levels of TNF produced upon PD-1 blockade further enhanced tumor cell killing when combined with birinapant. The combined anti-tumor activity of IAP antagonism and PD-1 blockade occurred independently of perforin-mediated tumor cell death. Taken together, we identify CL-derived TNF as a potent effector of birinapant mediated anti-tumor immunity and opportunity for combination therapy through co-inhibition of immune checkpoints.