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），截至2021年，全球最常见的癌症，占所有新的癌症的12％ 在全球范围内，年度癌症病例是美国女性最常见的癌症。基于 雌激素受体α（ERα），孕酮受体（PR）和人表皮生长的表达 因子受体2（HER2），乳腺癌可以分为三种主要亚型：腔内亚型（ERA/PR+， HER2-），HER2+子类型（ERA/HR-，HER2+）和三阴性亚型（TNBC，ERA/HR-，HER2-）。所有类型 BC具有转移性潜力。 TNBC是最致命的形式。化学抗性是治疗的主要障碍 功效。一旦化学耐药性发展，BC转移性便是无法治愈的。癌症免疫疗法已达到 在治疗包括TNBC在内的许多类型的高级癌症方面取得了前所未有的成功。但是，回应 卑诗省患者对癌症免疫疗法的率很低，因为肿瘤浸润的肿瘤渗透不良 淋巴细胞（TIL）。开发更有效的癌症免疫疗法方法对于治疗和治疗至关重要 TNBC患者。使用T细胞受体（TCR）-Alpha缺乏JA281 KO小鼠模型，我们发现转移 胸腺细胞进入JA281 KO小鼠可以完全抑制EO771和PY8119 TNBC在这些细胞中的生长 转移的小鼠。我们进一步发现，细胞转移引起的抗肿瘤免疫是由组织介导的 由移植的供体人群形成的居民αβ+CD4-CD8-双阴性T（DN T）细胞 破译基本机制将使我们能够发展一个强大的 TNBC治疗的免疫疗法方法。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。该项目的目的是解码 DN T细胞对TNBC的免疫抗病性。我们的中心假设是DN T细胞启动抗肿瘤免疫组织化学和 与NK细胞相互作用以控制TNBC生长并塑造肿瘤微环境（TME），并说 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 以下三个特定目标：目标1：确定如何生成组织居民的DN T细胞以及如何产生它们 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 组织居民DN T/NK细胞轴。 AIM 3：定义控制组织居民DN T的免疫调节细胞 细胞产生及其抗肿瘤功能。组织居住的DN T细胞可以抑制TNBC生长 放射性乳腺癌是新颖的。拟议的研究的完成不仅将大大进步 了解抗肿瘤免疫中DN T细胞的知识，但也使我们能够为TNBC开发更有效的方法 免疫疗法。