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

靶向ICOS/ICOSL途径改善抗肿瘤免疫反应

• 批准号: 8598462
• 负责人: PADMANEE SHARMA
• 金额: $ 31.8万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-29 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8598462
• 关键词: 1-Phosphatidylinositol 3-Kinase; Affect; Antigen-Presenting Cells; Antigens; Applications Grants; Autoimmunity; Autologous; B-Lymphocytes; Binding; CD28 gene; CD8B1 gene; Cancer Patient; Cell physiology; Cells; Clinical; Clinical Data; Clinical Trials; Collaborations; Combined Modality Therapy; Cytoplasmic Tail; Data; Development; Family; Foundations; Frequencies; Future; Goals; Human; Immune; Immune response; Immunoglobulins; Immunosuppression; Immunotherapy; In Vitro; Interferons; Interleukin-2; Knock-out; Knockout Mice; Lead; Ligands; Link; Manuscripts; Mediating; Monoclonal Antibodies; Mus; Pathway interactions; Patients; Play; Production; Publishing; Regulatory T-Lymphocyte; Reporting; Role; Signal Transduction; Structure of germinal center of lymph node; T cell response; T cell therapy; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; Tumor Immunity; Wild Type Mouse; base; cancer immunotherapy; cytokine; design; effective therapy; improved; innovation; member; mouse model; novel; novel therapeutics; pre-clinical; research study; response; tumor; tumor immunology

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.

描述（由申请人提供）：临床试验包括（1）用单克隆抗体阻断 CTLA-4 和（2）用体外扩增的自体 T 细胞进行过继性 T 细胞治疗，已在一组患者中证明了显着的抗肿瘤反应。这些疗法为开发更有效的免疫治疗策略奠定了基础，为患者提供更大的益处。 在我们的研究中，我们的重点是确定抗 CTLA-4 和过继性 T 细胞治疗后抗肿瘤反应的机制。与此应用相关，我们是第一个研究诱导共刺激分子 (ICOS) 分子在抗 CTLA-4 治疗过程中的作用的人。我们证明，一些患者表达 ICOS 的 T 细胞显着增加，并且 ICOS+ T 细胞的持续增加与临床获益相关。 ICOS是T细胞特异性分子，是CD28家族的成员。只有在激活后，ICOS 在 T 细胞上才会上调。它只有一种已知的配体，称为 ICOS 配体 (ICOSL)。 ICOS/ICOSL 通路被认为通过 ICOS 介导的 PI3 激酶信号传导影响 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，尚未有报道称 ICOS/ICOSL 通路在小鼠或人类抗肿瘤反应中发挥作用。 我们使用小鼠模型研究了 ICOS/ICOSL 通路在抗肿瘤反应中的作用，并证明 ICOS/ICOSL 通路在 CTLA-4 阻断的情况下在肿瘤免疫中发挥重要作用。抗 CTLA-4 治疗导致荷瘤野生型小鼠中 CD4+ICOS+ 和 CD8+ICOS+ T 细胞的频率增加。 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 IFN-。我们进一步证明ICOS/ICOSL途径对于最佳抗原特异性T细胞增殖和细胞因子产生至关重要。最重要的是，在 ICOS 敲除 (KO) 和 ICOSL-KO 小鼠中，CTLA-4 阻断诱导的抗肿瘤反应显着受损。该数据表明ICOS不仅仅是T细胞激活的标志物，而且还参与抗CTLA-4诱导的抗肿瘤作用。 因此，我们提供了第一个直接证据，表明在 CTLA-4 阻断的情况下，ICOS/ICOSL 途径是最佳抗肿瘤反应所必需的。我们现在假设 ICOS/ICOSL 途径由于 ICOS 介导的 PI3K 信号传导而诱导最佳的 T 细胞抗肿瘤反应。我们进一步假设 ICOS/ICOSL 通路可以靶向改善 CTLA-4 阻断以及过继性 T 细胞治疗的抗肿瘤反应。 因此，在当前的提案中，我们的目标是：1）阐明ICOS介导的PI3激酶信号在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； 3) 建立ICOS/ICOSL途径在过继性T细胞疗法中的相关性。