Targeting the ICOS/ICOSL pathway to improve anti-tumor immune responses

描述(由申请人提供)：临床试验包括(1)用单抗阻断CTLA-4和(2)用体外扩增的自体T细胞过继治疗T细胞，在一组患者中显示出显著的抗肿瘤反应。这些疗法为开发更有效的免疫治疗策略奠定了基础，为患者提供更大的好处。在我们的研究中，我们专注于确定抗CTLA-4和过继T细胞治疗后抗肿瘤反应的机制。针对这一应用，我们首次研究了可诱导共刺激分子(ICOS)在抗CTLA-4治疗中的作用。我们证明，一些患者表达ICOS的T细胞显著增加，ICOS+T细胞的持续增加与临床益处相关。ICOS是一种T细胞特异性分子，是CD28家族的成员。只有在T细胞被激活后，ICOS才会上调。它只有一个已知的配体，称为ICOS-配体(ICOSL)。ICOS/ICOSL通路被认为通过ICOS介导的PI3-K信号影响T细胞反应，但其在肿瘤免疫中的作用尚未确定。此外，在我们的研究之前，还没有报道ICOS/ICOSL通路在小鼠或人类抗肿瘤反应中发挥作用。我们利用小鼠模型研究了ICOS/ICOSL通路在抗肿瘤反应中的作用，并证明了ICOS/ICOSL通路在CTLA-4阻断的情况下在肿瘤免疫中起着重要作用。抗CTLA-4治疗导致荷瘤野生型小鼠的CD4+ICOS+和CD8+ICOS+T细胞频率增加。ICOS+T细胞主要产生Th1细胞因子，包括已知的抗肿瘤Th1细胞因子干扰素-。我们进一步证明ICOS/ICOSL通路对于抗原特异性T细胞的最佳增殖和细胞因子的产生是必不可少的。最重要的是，在ICOS基因敲除(KO)和ICOSL-KO小鼠中，CTLA-4阻断诱导的抗肿瘤反应显著减弱。这一数据表明，ICOS不仅仅是T细胞活化的标志，而且参与了抗CTLA-4诱导的抗肿瘤效应。因此，我们提供了第一个直接证据，证明在CTLA-4阻断的情况下，ICOS/ICOSL通路是最佳抗肿瘤反应所必需的。我们现在假设ICOS/ICOSL通路通过ICOS介导的PI3K信号通路诱导最佳的T细胞抗肿瘤反应。我们进一步假设ICOS/ICOSL通路可以在CTLA-4阻断和过继T细胞治疗的背景下靶向提高抗肿瘤反应。因此，在目前的建议中，我们的目标是：1)阐明ICOS介导的PI3-K信号在T细胞抗肿瘤反应中的作用；2)通过靶向ICOS/ICOSL途径结合CTLA-4阻断来改善抗肿瘤反应；以及3)建立ICOS/ICOSL途径在过继T细胞治疗中的相关性。

DESCRIPTION (provided by applicant): Clinical trials consisting of (1) CTLA-4 blockade with a monoclonal antibody and (2) adoptive T cell therapy with in vitro expanded autologous T cells have demonstrated dramatic anti-tumor responses in a susbset of patients. These therapies have laid the foundation for the development of more effective immunotherapy strategies to provide greater benefit to patients. In our studies we are focused on identifying the mechanisms that underlie the anti-tumor responses seen after anti-CTLA-4 and adoptive T cell therapy. Pertinent to this application, we were the first to investigate the role of the inducible costimulator (ICOS) molecule during anti-CTLA-4 therapy. We demonstrated that some patients had a significant increase in T cells expressing ICOS, and that a sustained increase in ICOS+ T cells correlated with clinical benefit. ICOS is a T cell specific molecule and a member of the CD28 family. ICOS is upregulated on T cells only after activation. It has only one known ligand referred to as ICOS-ligand (ICOSL). The ICOS/ICOSL pathway is thought to affect T cell responses via ICOS-mediated PI3-kinase signaling but a role for this in tumor immunity has not been established. Furthermore, prior to our studies, the ICOS/ICOSL pathway had not been reported to play a role in murine or human anti-tumor responses. We investigated the role of the ICOS/ICOSL pathway in anti-tumor responses using mouse models and demonstrated that the ICOS/ICOSL pathway plays an essential role in tumor immunity in the setting of CTLA-4 blockade. Anti-CTLA-4 therapy led to an increased frequency of CD4+ICOS+ and CD8+ICOS+ T cells in tumor- bearing wild-type mice. ICOS+ T cells predominantly produced Th1 cytokines including the known anti-tumor Th1 cytokine IFN- . We further demonstrated that the ICOS/ICOSL pathway was essential for optimal antigen- specific T cell proliferation and cytokine production. Most importantly, anti-tumor responses induced by CTLA-4 blockade were significantly impaired in ICOS-knockout (KO) and ICOSL-KO mice. This data establishes that ICOS is not a mere marker of T cell activation but is involved in the anti-tumor effect induced by anti-CTLA-4. We have thus provided the first direct evidence that the ICOS/ICOSL pathway is required for optimal anti-tumor responses in the setting of CTLA-4 blockade. We now hypothesize that the ICOS/ICOSL pathway induces optimal T cell anti-tumor responses due to ICOS-mediated PI3K signaling. We further hypothesize that the ICOS/ICOSL pathway can be targeted to improve anti-tumor responses in the setting of CTLA-4 blockade, as well as adoptive T cell therapy. Therefore, in the current proposal, we aim to: 1) Elucidate the role of ICOS-mediated PI3-kinase signaling in T cell anti-tumor responses; 2) Improve anti-tumor responses by targeting the ICOS/ICOSL pathway in combination with CTLA-4 blockade; and 3) Establish the relevance of the ICOS/ICOSL pathway in the setting of adoptive T cell therapy.