Target MIC shedding to revive anti-tumor immunity

靶向MIC脱落以恢复抗肿瘤免疫力

• 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
• 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

 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）：为了响应致癌应激，人类上皮细胞表达 MHC-I 链相关分子 MIC，通过接合自然杀伤 (NK) 细胞和效应 T 细胞上表达的激活免疫受体 NKG2D 来警告免疫系统。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。已充分证明，sMIC 通过下调 NK 上的 NKG2D 表达并影响 T 细胞，对免疫系统造成全局性损害。 sMIC 血清水平升高与许多癌症类型的疾病阶段相关。这些临床观察表明 sMIC 可能是癌症治疗靶点。然而，由于啮齿类动物中不存在人类 MIC 同源物这一主要障碍，靶向 sMIC 的概念迄今为止还无法在临床前进行测试。为了克服这一限制，我们生成并表征了“人源化”MIC/TRAMP双转基因小鼠模型，其中人MIC和癌基因在特定组织（前列腺）中同时表达。 TRAMP/MIC 小鼠在病理学和免疫学上与人类癌症患者非常相似，因此为我们提供了有效的临床前工具来评估 sMIC 是否是治疗靶点。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 扰乱肿瘤宿主中 NK 细胞的维持。 sMIC 的这种免疫抑制作用也在癌症患者中被发现。我们进一步发现 sMIC 刺激诱导 NK 细胞表达 PD-1，并且 PD-1 与其配体的连接会损害 NK 细胞的体外活力。基于这些初步观察，我们假设 PD-1 表达上调对癌症患者中 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 细胞并增强抗原特异性 CD8 T 细胞抗肿瘤反应。基于这些发现，我们进一步假设，针对 sMIC 和 PD-1 阻断的联合治疗可以通过释放免疫“检查点”制动器并同时重新设置 NK 细胞和 T 细胞免疫“引擎”来同时改变内源性抗肿瘤反应，从而产生协同抗肿瘤作用。我们计划通过三个具体目标来检验我们的假设：1）确定 sMIC 诱导 NK 细胞表达 PD-1 的机制； 2) 描绘PD-1信号传导对sMIC+肿瘤宿主NK细胞稳态的影响及其潜在的分子联系； 3) 评估PD-1阻断和靶向sMIC在MIC+肿瘤宿主中的联合治疗效果。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。