Targeting lymph node metastases to block cancer progression

针对淋巴结转移阻止癌症进展

• 批准号: 10743193
• 负责人: TIMOTHY P PADERA
• 金额: $ 49.93万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10743193
• 关键词: Automobile Driving; Biological Markers; Biometry; Blood Vessels; Breast Cancer Patient; CD4 Positive T Lymphocytes; CD86 gene; Cancer Patient; Cells; Data; Disseminated Malignant Neoplasm; Distant Metastasis; Ensure; Epithelium; Excision; Generations; Goals; High Endothelial Venule; Histocompatibility Antigens Class II; Immune; Immune response; Immunity; Immunology; Immunosuppression; Immunotherapy; Impairment; Infiltration; Interferon Type II; Invaded; Knock-out; Laboratories; Lesion; Losartan; Lymphocyte; Lymphocyte Activation; Lymphocyte Suppression; Lymphocytic Infiltrate; MHC Class II Genes; Maintenance; Malignant Lymph Node Neoplasm; Malignant Neoplasms; Measures; Metastatic Neoplasm to Lymph Nodes; Neoplasm Metastasis; Pathology; Pathway interactions; Patient-Focused Outcomes; Patients; Phenotype; Play; Prognosis; Publishing; Recommendation; Regulatory T-Lymphocyte; Research; Resources; Role; Signal Transduction; Systemic Therapy; Systems Biology; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Time; Tumor Immunity; Work; anti-cancer; cancer biomarkers; cancer cell; cellular engineering; clinical translation; clinically relevant; draining lymph node; immune checkpoint blockade; improved; inhibitor; lymph nodes; novel; novel therapeutics; patient subsets; prevent; programs; response; success; therapy development; therapy outcome; translational approach; tumor; tumor microenvironment; tumor progression

Utilizing the power of lymph nodes to generate long-lasting, systemic anti-cancer immune responses has the potential to eradicate metastatic cancers from patients as seen with the recent success of immunotherapy in a subset of patients. The presence of lymph node metastases, however, brings with it a worse prognosis and the recommendation for systemic therapy for most cancer patients. Over the past 5+years our laboratory has shown that—beyond being a biomarker of the aggressiveness of the cancer—lymph node metastases play previously unrecognized roles in cancer progression, including by escaping the lymph node and seeding distant metastases. Our preliminary data also show that metastatic lymph nodes are immune suppressed, which leads to poor systemic anti-cancer immune responses and allows cancer progression. For patients with lymph node metastasis, immune suppression of lymph nodes needs to be overcome for successful immunotherapy. For the proposed work, we have generated strong preliminary data for two complementary mechanisms that we hypothesize cancer cells use in metastatic lymph nodes to drive immune suppression. First, our data show that a subset of cancer cells in metastatic lymph nodes express MHC class II molecules but not co-stimulatory molecules. We hypothesize that interactions of MHCII positive cancer cells with naïve lymphocytes will lead to CD4 T-cell suppression and Treg formation, limiting anti-cancer immune responses (Aim 1). We will determine the consequences of MHCII expression on cancer cells in metastatic lymph nodes for anti-cancer immune responses. Second, our data show limited lymphocyte infiltration into metastatic lesions in lymph nodes due to remodeling of high-endothelial venules. Further, we show that losartan treatment can induce lymphocyte infiltration into lymph node metastases. In the proposed work, we will determine the mechanism driving lymphocytic infiltration after losartan treatment and test the hypothesis that these infiltrated lymphocytes can be activated to promote anti-cancer immune responses (Aim 2). Finally, to generate an anti-cancer immune response against metastatic lymph node lesions, both lymphocytic activation (Aim 1) and infiltration (Aim 2) are required. Improving only one will likely not be sufficient to drive an anti-cancer immune response. Thus, we will test translational approaches to inhibit MHCII cancer cell expression to prevent suppression of lymphocytic immune response in combination with losartan to drive lymphocytic infiltration of metastatic lymph nodes (Aim 3). Our novel research program will discover critical mechanisms of immune suppression of metastatic lymph nodes as well as develop therapeutic strategies to overcome these mechanisms. To achieve these goals, we have assembled a world-class team of experts in lymph node metastasis (T. Padera), immunology (Mempel), cancer microenvironment (Jain), systems biology (Beyaz), pathology (R. Padera), clinical translation (Taghian) and biostatistics (Lee). The collective expertise and resources of the team will ensure successful completion of the proposed Aims and the exploration of novel treatment approaches for patients with metastatic cancer.

利用淋巴结的力量产生持久的、全身性的抗癌免疫反应具有以下优势： 免疫疗法最近在一些领域取得的成功证明了从患者身上根除转移性癌症的潜力 患者的子集。然而，淋巴结转移的存在会带来更差的预后和 对大多数癌症患者进行全身治疗的建议。在过去 5 年多的时间里，我们的实验室已经证明 除了作为癌症侵袭性的生物标志物之外，淋巴结转移也曾发挥过作用 在癌症进展中未被认识到的作用，包括逃避淋巴结和远处播散 转移。我们的初步数据还表明，转移淋巴结受到免疫抑制，这导致 全身抗癌免疫反应不佳，导致癌症进展。对于有淋巴结的患者 为了成功的免疫治疗，需要克服淋巴结的转移、免疫抑制。对于 拟议的工作中，我们已经为我们的两个补充机制生成了强有力的初步数据 假设癌细胞在转移淋巴结中利用来驱动免疫抑制。首先，我们的数据表明 转移淋巴结中的一部分癌细胞表达 MHC II 类分子，但不表达共刺激分子 分子。我们假设 MHCII 阳性癌细胞与幼稚淋巴细胞的相互作用将导致 CD4 T 细胞抑制和 Treg 形成，限制抗癌免疫反应（目标 1）。我们将确定 MHCII 表达对转移淋巴结癌细胞抗癌免疫的影响 回应。其次，我们的数据显示，由于以下原因，淋巴细胞浸润到淋巴结转移灶中有限： 高内皮小静脉的重塑。此外，我们表明氯沙坦治疗可以诱导淋巴细胞 浸润至淋巴结转移。在拟议的工作中，我们将确定驱动机制 氯沙坦治疗后淋巴细胞浸润，并检验这些浸润的淋巴细胞可以被 激活以促进抗癌免疫反应（目标 2）。最后，产生抗癌免疫 针对转移性淋巴结病变的反应，淋巴细胞活化（目标 1）和浸润（目标 2） 必需的。仅改善其中一项可能不足以驱动抗癌免疫反应。这样，我们将 测试抑制 MHCII 癌细胞表达以防止淋巴细胞抑制的转化方法 免疫反应与氯沙坦联合驱动转移淋巴结的淋巴细胞浸润（目标 3）。我们的新研究计划将发现转移性淋巴免疫抑制的关键机制 节点并制定治疗策略来克服这些机制。为了实现这些目标，我们 组建了淋巴结转移（T. Padera）、免疫学（Mempel）方面世界一流的专家团队， 癌症微环境 (Jain)、系统生物学 (Beyaz)、病理学 (R. Padera)、临床翻译 (Taghian) 和生物统计学（李）。团队的集体专业知识和资源将确保成功完成 拟议的目标以及对转移性癌症患者新治疗方法的探索。