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.

利用淋巴结的力量来产生持久的、系统性的抗癌免疫反应