Target MIC shedding to revive anti-tumor immunity

靶向MIC脱落以恢复抗肿瘤免疫力

基本信息

批准号：
10408690
负责人：
JENNIFER D WU
金额：
$ 30.55万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10408690
关键词：
Adopted Adoptive Transfer Antibodies Antigens Antitumor Response Autoimmunity Biochemical Biology CD8-Positive T-Lymphocytes Cancer Patient Cell Maintenance Cell Proliferation Cell Survival Cell physiology Cell surface Cells Cellular biology Clinical Clinical Trials Cytotoxic T-Lymphocytes Data Disease Epithelial Epithelial Cells Future Homeostasis Homologous Gene Human Immune Immune system Immunity Immunologic Receptors Immunologic Surveillance Immunologics Impairment In Vitro Isogenic transplantation Killer Cells Ligands Ligation Light Link Maintenance Malignant Neoplasms Mediating Membrane Modeling Molecular Mus Nature Neoplasm Metastasis Neoplasm Transplantation Oncogenes Oncogenic Outcome PD-1 blockade PD-1 pathway PD-1/PD-L1 PD-L1 blockade Pathologic Pathway interactions Patients Peptide Hydrolases Peripheral Preclinical Testing Primary Neoplasm Prostate Publishing Reporting Rodent Serum Shapes Signal Transduction Stress Surface T cell response T-Lymphocyte Testing Therapeutic Therapeutic Effect Therapeutic Monoclonal Antibodies Tissues Transgenic Mice Transgenic Organisms Translating Translations Transplantation Treatment Efficacy Tumor Escape Tumor Immunity Tumor-Derived Up-Regulation antitumor effect base cancer cell cancer immunotherapy cancer type clinical application clinical practice cytokine effector T cell exhaustion immune activation immune checkpoint improved innovation insight mouse model neoplastic cell neutralizing antibody neutralizing monoclonal antibodies novel pre-clinical programmed cell death protein 1 public health relevance receptor response targeted treatment therapeutic target tool tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): In response to oncogenic stress, human epithelial cells express the MHC-I chain related molecule, MIC, to alert the immune system by engaging the activation immune receptor NKG2D expressed on nature killer (NK) cells and effector T cells. However, human cancer cells broadly adopt a strategy to evade NKG2D-mediated immunity by shedding surface MIC to produce soluble MIC (sMIC). It has been well demonstrated that sMIC poses global insults to the immune system by down-regulating NKG2D expression on NK and effect T cells. Elevated serum levels of sMIC correlates with disease stages in many cancer types. These clinical observations suggested that sMIC may be a cancer therapeutic target. However, due to the major obstacle that no human MIC homolog is present in rodents, the concept of targeting sMIC cannot be tested pre-clinically until now. To overcome this limitation, we have generated and characterized a "humanized" MIC/TRAMP bi- transgenic mouse model in which human MIC and the oncogene concurrently expressed in a specific tissue, the prostate. The TRAMP/MIC mice closely resemble human cancer patients pathologically and immunologically and thus provide us with a valid preclinical tool to evaluate whether sMIC is a therapeutic target. With the TRAMP/MIC mouse model, we also uncovered the novel sMIC immune suppressive effect whereby sMIC perturbs NK cell maintenance in tumor host. This immune suppressive effect of sMIC is also found in cancer patients. We further found that sMIC stimulation induces PD-1 expression on NK cells and that ligation of PD-1 by its ligands impairs NK cell viability in vitro. Based on these preliminary observations, we hypothesize that upregulation of PD-1 expression contributes significantly to sMIC-mediated perturbation of NK cell maintenance in cancer patients. Importantly, we have developed a sMIC-neutralizing monoclonal antibody which we have shown to effectively revive host NK cells and potentiate antigen-specific CD8 T cell anti-tumor responses. Based on these findings, we further hypothesize that a combinatory therapy of targeting sMIC and PD-1 blockade can generate synergistic anti-tumor effect through releasing immune "check-point" brake and simultaneously re-setting the NK cell and T cell immunity "the engine" to concurrently revamp endogenous anti-tumor responses. We plan to test our hypothesis with three Specific Aims: 1) To determine the mechanisms whereby sMIC induces PD-1 expression on NK cells; 2) To delineate the impact of PD-1 signaling on NK cell homeostasis in sMIC+ tumor host and the underlying molecular link; 3) To evaluate the combinatory therapeutic efficacy of PD-1 blockade and targeting sMIC in MIC+ tumor host. Our proposed study will not only uncover novel understandings of NKG2D and NK cell biology, but also will have significant and potentially immediate clinical implications in translating NKG2D tumor immunity into clinical practices.

描述（由申请人提供）：为了应对致癌应激，人类上皮细胞表达 MHC-I 链相关分子 MIC，通过激活自然杀伤 (NK) 细胞和效应 T 细胞上表达的免疫受体 NKG2D 来提醒免疫系统然而，人类癌细胞广泛采用一种策略，通过脱落表面 MIC 产生可溶性 MIC (sMIC) 来逃避 NKG2D 介导的免疫。 sMIC 已被充分证明。通过下调 NK 上的 NKG2D 表达并影响 T 细胞，对免疫系统造成整体损害。 sMIC 的血清水平升高与许多癌症类型的疾病阶段相关。由于啮齿动物中不存在人类 MIC 同源物的主要障碍，靶向 sMIC 的概念迄今为止无法在临床前进行测试。为了克服这一限制，我们已经产生并表征了“人源化”。 MIC/TRAMP 双转基因小鼠模型，其中人类 MIC 和癌基因同时在特定组织（前列腺）中表达。TRAMP/MIC 小鼠在病理学和免疫学上与人类癌症患者非常相似，从而为我们提供了有效的临床前工具来评估是否存在这种情况。 sMIC 是一个治疗靶点，通过 TRAMP/MIC 小鼠模型，我们还发现了新的 sMIC 免疫抑制作用，即 sMIC 扰乱了肿瘤宿主中 NK 细胞的维持。 sMIC 也存在于癌症患者中，我们进一步发现 sMIC 刺激会诱导 NK 细胞表达 PD-1，并且其配体连接 PD-1 会损害 NK 细胞的体外活力。 PD-1 表达对癌症患者中 sMIC 介导的 NK 细胞维持扰动有显着贡献。重要的是，我们开发了一种 sMIC 中和单克隆抗体，我们已证明该抗体可以有效恢复宿主 NK。基于这些发现，我们进一步发现，针对 sMIC 和 PD-1 阻断的联合疗法可以通过释放免疫“检查点”制动来产生协同抗肿瘤作用。并同时重置 NK 细胞和 T 细胞免疫“引擎”，同时改进内源性抗肿瘤反应。我们计划通过三个具体目标来检验我们的假设：1）确定 sMIC 的机制。诱导 NK 细胞上的 PD-1 表达；2) 描述 PD-1 信号传导对 sMIC+ 肿瘤宿主中 NK 细胞稳态的影响以及潜在的分子联系；3) 评估 PD-1 阻断和靶向 sMIC 的联合治疗效果我们提出的研究不仅将揭示对 NKG2D 和 NK 细胞生物学的新理解，而且还将具有重大且潜在的直接临床意义。将 NKG2D 肿瘤免疫转化为临床实践。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The CXCL8-CXCR1/2 pathways in cancer.

癌症中的 CXCL8-CXCR1/2 通路。

DOI：
发表时间：
2016
期刊：
影响因子：
13
作者：
Liu, Qian;Li, Anping;Tian, Yijun;Wu, Jennifer D;Liu, Yu;Li, Tengfei;Chen, Yuan;Han, Xinwei;Wu, Kongming
通讯作者：
Wu, Kongming