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: 8435361
• 负责人: PADMANEE SHARMA
• 金额: $ 30.82万
• 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/8435361
• 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）：由（1）CTLA-4与单克隆抗体进行阻断和（2）通过体外扩展的自体T细胞的过养T细胞疗法组成的临床试验表明，患者的susbset表现出了戏剧性的抗肿瘤反应。这些疗法为制定更有效的免疫疗法策略奠定了基础，以为患者提供更大的好处。 在我们的研究中，我们专注于确定在抗CTLA-4和收养T细胞疗法后看到的抗肿瘤反应的机制。与此应用有关，我们是第一个研究抗CTLA-4治疗期间诱导型共刺激剂（ICO）分子的作用的人。我们证明，某些患者表达ICO的T细胞显着增加，并且ICOS+ T细胞的持续增加与临床益处相关。 ICOS是T细胞特异性分子，也是CD28家族的成员。 ICO仅在激活后才在T细胞上上调。它只有一个称为ICOS-配体（ICOSL）的已知配体。 ICOS/ICOSL途径被认为通过ICOS介导的PI3-激酶信号传导影响T细胞反应，但尚未确定该途径在肿瘤免疫中的作用。此外，在我们的研究之前，尚未据报道ICOS/ICOSL途径在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途径在抗肿瘤响应中的作用，并证明ICOS/ICOSL途径在CTLA-4阻滞的情况下在肿瘤免疫中起着至关重要的作用。抗CTLA-4治疗导致野生型小鼠的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的产生至关重要。最重要的是，在ICOS-KNOCKOUT（KO）和ICOSL-KO小鼠中，由CTLA-4阻断引起的抗肿瘤反应受到了显着损害。该数据表明，ICO不仅仅是T细胞激活的标记，而是参与抗CTLA-4引起的抗肿瘤效应。 因此，我们提供了第一个直接的证据，表明在CTLA-4阻滞中，ICOS/ICOSL途径是最佳的抗肿瘤响应所必需的。现在，我们假设ICOS/ICOSL途径诱导ICOS介导的PI3K信号引起的最佳T细胞抗肿瘤反应。我们进一步假设，ICOS/ICOSL途径可以针对CTLA-4阻断和收养T细胞疗法的抗肿瘤反应。 因此，在当前的建议中，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）通过将ICOS/ICOSL途径与CTLA-4阻滞结合使用，改善抗肿瘤反应； 3）确定ICOS/ICOSL途径在产物T细胞疗法的情况下的相关性。