Combined targeting of costimulatory (OX40) and coinhibitory (CTLA-4) pathways elicits potent effector T cells capable of driving robust antitumor immunity.
Combined targeting of costimulatory (OX40) and coinhibitory (CTLA-4) pathways elicits potent effector T cells capable of driving robust antitumor immunity.
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DOI：
10.1158/2326-6066.cir-13-0031-t
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发表时间：
2014-02
影响因子：
10.1
通讯作者：
Kasiewicz MJ
中科院分区：
文献类型：
--
作者：
Redmond WL;Linch SN;Kasiewicz MJ
TNF受体家族共刺激分子OX 40（CD 134）与激动剂抗OX 40 mAb的连接通过增强T细胞分化以及关闭FoxP 3 + CD 4+调节性T细胞（Treg）的抑制活性来增强抗肿瘤免疫力。此外，抗体介导的检查点抑制剂CTLA-4的阻断释放了T细胞上的“刹车”，以增强肿瘤免疫治疗。然而，这些药物的单一疗法具有有限的治疗益处，特别是针对免疫原性差的鼠肿瘤。因此，我们检查了在CTLA-4阻断的情况下给予激动剂抗OX 40治疗是否会增强肿瘤免疫治疗。联合抗OX 40/抗CTLA-4免疫疗法以CD 4和CD 8 T细胞依赖性方式显著增强肿瘤消退和荷瘤宿主的存活。机制研究表明，联合免疫疗法指导效应T-behigh/Eomeshigh颗粒酶B+ CD 8 T细胞的扩增。双重免疫疗法还在Th 1（IL-2、IFNγ）和令人惊讶的Th 2（IL-4、IL-5和IL-13）CD 4 T细胞的不同群体中诱导，表现出增加的T-bet和加塔-3表达。此外，IL-4阻断抑制了Th 2应答，同时维持了Th 1 CD 4和效应CD 8 T细胞，从而提高了无肿瘤存活率。这些数据表明，在联合免疫治疗期间改善整体T细胞应答可以进一步增强这些药物的治疗功效。
Ligation of the TNF receptor family co-stimulatory molecule OX40 (CD134) with an agonist anti-OX40 mAb enhances antitumor immunity by augmenting T cell differentiation as well as turning off the suppressive activity of the FoxP3+CD4+ regulatory T cells (Treg). In addition, antibody-mediated blockade of the checkpoint inhibitor CTLA-4 releases the “brakes” on T cells to augment tumor immunotherapy. However, monotherapy with these agents have limited therapeutic benefit particularly against poorly immunogenic murine tumors. Therefore, we examined whether the administration of agonist anti-OX40 therapy in the presence of CTLA-4 blockade would enhance tumor immunotherapy. Combined anti-OX40/anti-CTLA-4 immunotherapy significantly enhanced tumor regression and the survival of tumor-bearing hosts in a CD4 and CD8 T cell-dependent manner. Mechanistic studies revealed that the combination immunotherapy directed the expansion of effector T-bethigh/Eomeshigh granzyme B+ CD8 T cells. Dual immunotherapy also induced among distinct populations of Th1 (IL-2, IFNγ) and, surprisingly, Th2 (IL-4, IL-5, and IL-13) CD4 T cells exhibiting increased T-bet and Gata-3 expression. Furthermore, IL-4 blockade inhibited the Th2 response, while maintaining the Th1 CD4 and effector CD8 T cells that enhanced tumor-free survival. These data demonstrate that refining the global T cell response during combination immunotherapy can further enhance the therapeutic efficacy of these agents.