Probing the Role of TIM-4 in Cross-Presentation of Tumor-Associated Antigens

探讨 TIM-4 在肿瘤相关抗原交叉呈递中的作用

• 批准号: 8699727
• 负责人: Scott McNabb Loughhead
• 金额: $ 3万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8699727
• 关键词: Antigen Presentation; Antigen Presentation Pathway; Antigen Targeting; Antigens; Apoptotic; Autologous Dendritic Cells; CD8B1 gene; Cells; Characteristics; Clinical; Cross Presentation; Cross-Priming; Cytolysis; Cytotoxic T-Lymphocytes; Dendritic Cells; Development; Disease; Endocytosis; Environment; Generations; Goals; Immune system; Immunity; Immunoglobulin Domain; Immunoglobulins; Immunologic Monitoring; Immunologic Surveillance; Immunosuppressive Agents; In Vitro; Injection of therapeutic agent; Knowledge; Lead; Link; Lymphocyte Activation; Malignant Neoplasms; Measures; Microscopy; Modeling; Molecular; Mucins; Mus; Pathway interactions; Patients; Population Heterogeneity; Process; Proteins; Protocols documentation; Regulatory Pathway; Research; Role; Signal Transduction; Stimulus; Symptoms; T-Lymphocyte; Testing; Therapeutic; Transgenic Organisms; Tumor Antigens; Tumor Volume; Vaccines; Viral Vector; Virus Diseases; Work; base; cancer therapy; immunogenic; immunogenicity; in vivo; in vivo Model; lymph nodes; mouse model; nanoparticle; neoplastic cell; particle; phosphatidylserine receptor; pressure; research study; response; success; tumor; two-photon; uptake

DESCRIPTION (provided by applicant): Cancer is a disease that develops in a stepwise fashion as a heterogeneous population of cells slowly overcomes the regulatory circuits that normally bar cells from limitless replicative potential. One such regulatory pathway is that of immune surveillance. There is now good evidence from mouse models that the immune system places pressure on the development of cancer and can maintain it in an occult state. Cytolytic T lymphocytes (CTLs) and their effector proteins have been shown to be at least partially responsible for this effect. The clinical symptoms of cancer, however, arise after the tumor has established an immunosuppressive environment that is able to circumvent these pressures. Therapies targeting this pathway have sought to prime and reinvigorate CTL responses using viral vectors or by loading autologous dendritic cells (DCs) with tumor-associated antigens and re-injecting them into the patient. These therapies have shown efficacy in some patients, demonstrating the feasibility of such a protocol. Although feasible, success rates have been disappointing and current work seeks to target antigens to the relevant DC subsets in vivo for efficient generation of antitumor CTLs. The CD8alpha DC subset is a promising candidate, given its ability to acquire exogenous antigens for presentation to CTLs, a process termed cross-presentation. This unique ability has, at least in part, been attributed to its ability to endocytose apoptotic cells. These two characteristics, however, have been difficult to mechanistically link since the molecular requirements for this engulfment are not understood. It is generally believed that CD8alpha DCs express a receptor for phosphatidylserine (PS), a prominent feature of apoptotic cells, which could explain this phenomenon. Our preliminary in vitro experiments demonstrate that T cell immunoglobulin domain and mucin doman-4 (TIM-4), a PS receptor, is preferentially expressed by CD8alpha DCs upon maturation and that inhibition of TIM-4 function leads to inefficient uptake of apoptotic cells and defective cross-presentation of these cell-associated antigens. Aim 1 will establish whether and to what extent TIM-4 contributes to cross-presentation of apoptotic cell-associated antigens and subsequent generation of CTL immunity in vivo. Aim 2 will seek to test whether TIM-4 can be used to target antigens to CD8alpha DCs for efficient cross-presentation and subsequent rejection of tumors. If our hypotheses can be proven correct, these experiments will add to our understanding of the molecular requirements for immunosurveillance and provide a possible basis for cancer treatment.

描述（由申请人提供）：癌症是一种以逐步发展的方式发展的疾病，因为异质细胞群缓慢地克服了通常阻止细胞无限复制潜力的调节回路。其中一种调控途径是免疫监视。现在，从小鼠模型中有很好的证据表明，免疫系统对癌症的发展施加压力，并能将其维持在一种隐蔽的状态。细胞溶解性T淋巴细胞（ctl）及其效应蛋白已被证明至少部分负责这种作用。然而，癌症的临床症状是在肿瘤建立了能够规避这些压力的免疫抑制环境后出现的。针对这一途径的治疗已经寻求利用病毒载体或通过装载自体树突状细胞（dc）与肿瘤相关抗原并将其重新注射到患者体内来启动和重振CTL反应。这些疗法在一些患者中显示出疗效，证明了这种方案的可行性。虽然可行，但成功率令人失望，目前的工作是寻求将抗原靶向到体内相关的DC亚群，以有效地产生抗肿瘤ctl。CD8alpha DC亚群是一个很有希望的候选者，因为它能够获得外源抗原，并将其呈递到ctl，这一过程被称为交叉呈递。这种独特的能力至少部分归因于其内吞凋亡细胞的能力。然而，这两个特征很难在机械上联系起来，因为这种吞没的分子要求尚不清楚。一般认为CD8alpha dc表达一种磷脂酰丝氨酸（PS）受体，这是凋亡细胞的一个显著特征，可以解释这一现象。我们的初步体外实验表明，T细胞免疫球蛋白结构域和粘蛋白结构域-4 (TIM-4)，一种PS受体，在成熟时被CD8alpha dc优先表达，抑制TIM-4功能导致凋亡细胞的低效摄取和这些细胞相关抗原的缺陷交叉呈递。目的1将确定TIM-4是否以及在多大程度上有助于体内凋亡细胞相关抗原的交叉呈递和随后的CTL免疫的产生。Aim 2将寻求测试TIM-4是否可以用于靶向CD8alpha dc的抗原，以实现有效的交叉呈递和随后的肿瘤排斥。如果我们的假设可以被证明是正确的，这些实验将增加我们对免疫监视分子需求的理解，并为癌症治疗提供可能的基础。