Mechanism of double-negative T cells in antitumor immunity to breast cancer

双阴性T细胞在乳腺癌抗肿瘤免疫中的作用机制

• 批准号: 10735679
• 负责人: Hui Zhang
• 金额: $ 36.49万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10735679
• 关键词: Accounting; Advanced Malignant Neoplasm; American; Antitumor Response; Biology; Breast Cancer Patient; Breast Cancer Treatment; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Chemoresistance; Classification; Clinical; Combination immunotherapy; Complex; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Development; Disease; Donor person; EO771; Early treatment; Epidermal Growth Factor Receptor; Estrogen Receptor alpha; Exhibits; Family; Foundations; Generations; Goals; Growth; Human; Immune; Immune checkpoint inhibitor; Immune system; Immunotherapeutic agent; Immunotherapy; Infiltration; Knockout Mice; Knowledge; Lymphoma; Macrophage; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Metastatic breast cancer; Methods; Modeling; Molecular; Mucous Membrane; Mus; Natural Killer Cells; Non-Small-Cell Lung Carcinoma; Patients; Play; Population; Pre-Clinical Model; Progesterone Receptors; Regimen; Regulatory T-Lymphocyte; Reporting; Research; Resistance development; Role; Shapes; Solid; T cell response; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; T-cell receptor repertoire; Testing; Tissues; Treatment Efficacy; Tumor Immunity; Tumor-Infiltrating Lymphocytes; Wild Type Mouse; Woman; anti-PD-1; anti-tumor immune response; antitumor effect; cancer diagnosis; cancer immunotherapy; cancer therapy; chemotherapy; immunogenic; immunoregulation; improved; improved outcome; innovation; malignant breast neoplasm; melanoma; mouse model; novel; response; success; survival outcome; thymocyte; triple-negative invasive breast carcinoma; tumor; tumor immunology; tumor microenvironment; tumor progression

Abstract: Breast cancer (BC), the most common cancer globally as of 2021 and accounting for 12% of all new annual cancer cases worldwide, is the most commonly diagnosed cancer among American women. Based on the expression of estrogen receptor alpha (ERα), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), breast cancer can be classified into three major subtypes: luminal subtype (ERa/PR+, HER2-), HER2+ subtype (ERa/HR-, HER2+), and triple-negative subtype (TNBC, ERa/HR-, HER2-). All types of BC have metastatic potential. TNBC is the deadliest form. Chemoresistance is a major obstacle to therapeutic efficacy. Once chemoresistance develops, metastatic BC is incurable. Cancer immunotherapy has achieved unprecedented success in treating many types of advanced cancers, including TNBC. However, the response rate of BC patients to cancer immunotherapy is low because of the poor tumor infiltration of tumor-infiltrating lymphocytes (TIL). Developing more effective cancer immunotherapy approaches is critical to treating and curing TNBC patients. Using a T cell receptor (TCR)-alpha deficient Ja281 KO mouse model, we found that transferring thymocytes into Ja281 KO mice could completely inhibit EO771 and Py8119 TNBC growth in these cell- transferred mice. We further found that the cell transfer-induced antitumor immunity was mediated by tissue- resident αβ+CD4-CD8- double-negative T (DN T) cells formed from the transplanted donor population and depended on host NK cells. Deciphering the underlying mechanism will allow us to develop a powerful immunotherapy approach for TNBC treatment. The long-term goal of our research is to develop new immunotherapeutic regimens for cancer treatment. The objective of this project is to decode the mechanism of DN T cell antitumor immunity to TNBC. Our central hypothesis is that DN T cells initiate antitumor immunity and interact with NK cells to control TNBC growth and to shape tumor microenvironment (TME) and that a population of immunoinhibitory T cells modulate DN T cell antitumor function. We will test this hypothesis by pursuing the following three specific aims: Aim 1: Determine how tissue-resident DN T cells are generated and how they mediate antitumor immunity using the Ja281 KO mouse model. Aim 2. Determine the antitumor function of tissue-resident DN T/NK cell axis. Aim 3: Define the immunoregulatory cells that govern tissue-resident DN T cell generation and their antitumor function. The finding that tissue-resident DN T cells can inhibit TNBC growth and eradicate breast cancer is novel. The completion of the proposed research will not only greatly advance our knowledge of DN T cells in antitumor immunity, but also allow us to develop more effective approaches for TNBC immunotherapy.

摘要：乳腺癌 (BC) 是截至 2021 年全球最常见的癌症，占所有新发癌症的 12% 全球每年的癌症病例是美国女性中最常诊断出的癌症。基于 雌激素受体α（ERα）、孕激素受体（PR）的表达和人表皮生长 因子受体2（HER2），乳腺癌可分为三大亚型：管腔亚型（ERa/PR+、 HER2-）、HER2+ 亚型（ERa/HR-、HER2+）和三阴性亚型（TNBC、ERa/HR-、HER2-）。所有类型的 BC有转移潜力。 TNBC 是最致命的形式。化疗耐药是治疗的主要障碍 功效。一旦出现化疗耐药性，转移性乳腺癌就无法治愈。癌症免疫疗法已取得 在治疗包括 TNBC 在内的多种晚期癌症方面取得了前所未有的成功。然而，回应 由于肿瘤浸润性差，BC患者接受癌症免疫治疗的比例较低 淋巴细胞（TIL）。开发更有效的癌症免疫治疗方法对于治疗和治愈至关重要 三阴性乳腺癌患者。使用 T 细胞受体 (TCR)-α 缺陷型 Ja281 KO 小鼠模型，我们发现转移 将胸腺细胞注入 Ja281 KO 小鼠中可以完全抑制这些细胞中 EO771 和 Py8119 TNBC 的生长 转移小鼠。我们进一步发现细胞转移诱导的抗肿瘤免疫是由组织介导的 由移植供体群体形成的常驻 αβ+CD4-CD8- 双阴性 T (DN T) 细胞和 取决于宿主 NK 细胞。破译底层机制将使我们能够开发出强大的 TNBC 治疗的免疫治疗方法。我们研究的长期目标是开发新的 用于癌症治疗的免疫治疗方案。该项目的目标是解码 DN T 细胞对 TNBC 的抗肿瘤免疫。我们的中心假设是 DN T 细胞启动抗肿瘤免疫并 与 NK 细胞相互作用，控制 TNBC 生长并塑造肿瘤微环境 (TME)，并且群体 免疫抑制性 T 细胞调节 DN T 细胞抗肿瘤功能。我们将通过追求 以下三个具体目标： 目标 1：确定组织驻留 DN T 细胞是如何产生的以及它们是如何产生的 使用 Ja281 KO 小鼠模型介导抗肿瘤免疫。目标2.确定抗肿瘤功能 组织驻留 DN T/NK 细胞轴。目标 3：定义控制组织驻留 DN T 的免疫调节细胞 细胞生成及其抗肿瘤功能。组织驻留 DN T 细胞可以抑制 TNBC 生长的发现 根除乳腺癌是新颖的。拟议研究的完成不仅将极大地推进我们的工作 DN T 细胞在抗肿瘤免疫方面的知识，也使我们能够开发出更有效的 TNBC 方法 免疫疗法。