The ICOS/ICOSL Pathway Is Required for Optimal Antitumor Responses Mediated by Anti-CTLA-4 Therapy
The ICOS/ICOSL Pathway Is Required for Optimal Antitumor Responses Mediated by Anti-CTLA-4 Therapy
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DOI：
10.1158/0008-5472.can-11-1138
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发表时间：
2011-08-15
期刊：
影响因子：
11.2
通讯作者：
Sharma, Padmanee
中科院分区：
文献类型：
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作者：
Fu, Tihui;He, Qiuming;Sharma, Padmanee
抗CTL相关抗原4（抗CTLA-4）抗体ipilimumab是第一个在随机III期试验中显示出改善生存率的药物，该试验招募了转移性黑色素瘤患者。正在进行研究以确定在抗CTLA-4治疗的背景下引起临床益处的机制。我们以前报道过，接受治疗的患者表达诱导型共刺激分子（ICOS）的T细胞频率增加，ICOS是一种属于CD28/CTLA-4/B7免疫球蛋白超家族的T细胞特异性分子。已证明ICOS及其配体（IXSL）在T细胞反应中发挥多种作用，例如介导自身免疫以及增强调节性T细胞的发育/活性。这些看似相反的作用使得很难确定ICOS/ICOSL通路是否是抗肿瘤反应所必需的。为了确定ICOS/ICOSL通路是否可能在抗CTLA-4介导的抗肿瘤作用中发挥因果作用，我们在携带B16/BL6黑色素瘤的ICOS充足和ICOS缺陷小鼠中进行了研究。我们表明，ICOS + T细胞包括一个人口的Th1细胞因子产生和肿瘤抗原特异性效应细胞。此外，在不存在ICOS的情况下，由抗CTLA-4引发的抗肿瘤T细胞应答显著减少，从而削弱肿瘤排斥。我们的研究结果表明，ICOS/ICOSL途径是抗CTLA-4的最佳治疗效果所必需的，因此暗示该途径是未来提高抗CTLA-4治疗疗效的组合策略的靶点。Cancer Res; 71（16）; 5445 - 54. (c)2011年AACR。
The anti-CTL-associated antigen 4 (anti-CTLA-4) antibody ipilimumab is the first agent to show improved survival in a randomized phase III trial that enrolled patients with metastatic melanoma. Studies are ongoing to identify mechanisms that elicit clinical benefit in the setting of anti-CTLA-4 therapy. We previously reported that treated patients had an increase in the frequency of T cells expressing the inducible costimulator (ICOS) molecule, a T-cell-specific molecule that belongs to the CD28/CTLA-4/B7 immunoglobulin superfamily. ICOS and its ligand (ICOSL) have been shown to play diverse roles in T-cell responses such as mediating autoimmunity as well as enhancing the development/activity of regulatory T cells. These seemingly opposing roles have made it difficult to determine whether the ICOS/ICOSL pathway is necessary for antitumor responses. To determine whether the ICOS/ICOSL pathway might play a causal role in the antitumor effects mediated by anti-CTLA-4, we conducted studies in ICOS-sufficient and ICOS-deficient mice bearing B16/BL6 melanoma. We show that ICOS+ T cells comprised a population of Th1 cytokine producing and tumor antigen-specific effector cells. Furthermore, in the absence of ICOS, antitumor T-cell responses elicited by anti-CTLA-4 are significantly diminished, thereby impairing tumor rejection. Our findings establish that the ICOS/ICOSL pathway is necessary for the optimal therapeutic effect of anti-CTLA-4, thus implicating this pathway as a target for future combinatorial strategies to improve the efficacy of anti-CTLA-4 therapy. Cancer Res; 71(16); 5445-54. (c) 2011 AACR.