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Paradoxical roles of tumor lymphangiogenesis on tumor immunity and implications for immunotherapy - Resubmission 01

肿瘤淋巴管生成对肿瘤免疫的矛盾作用及其对免疫治疗的影响 - 重新提交 01

基本信息

批准号：
9891035
负责人：
Melody Ann Swartz
金额：
$ 37.06万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9891035
关键词：
Affect Antigens Automobile Driving Binding Bioinformatics Biophysics Blocking Antibodies Blood CCL21 gene Cell Compartmentation Cell Survival Cells Clinical Research Data Dendritic Cell Vaccine Dendritic Cells Development Environment Epitope spreading Growth Factor Homing Human Immune Immune checkpoint inhibitor Immunity Immunosuppression Immunotherapy Infiltration Inflammatory Lymphangiogenesis Lymphatic Lymphoid Malignant Neoplasms Memory Modeling Mus Neoplasm Metastasis Patients Phenotype Play Predisposition Prospective Studies Proteins Reporting Research Resistance Role Route Serum Shapes Side Signal Transduction Specificity Structure T cell therapy T memory cell T-Cell Activation T-Lymphocyte T-cell inflamed Therapeutic Tissues Tumor Immunity Tumor-infiltrating immune cells Up-Regulation Vaccination Vaccines Validation Variant Vascular Endothelial Growth Factor C Vascular Endothelial Growth Factor Receptor-3 beta catenin cancer immunotherapy cell killing chemokine cytokine immune checkpoint blockade immunogenic lymph nodes lymphatic vessel melanoma mouse model nanoparticle neoplastic cell novel novel therapeutics outcome forecast overexpression predicting response programs receptor recruit response tumor tumor microenvironment tumor progression tumor-immune system interactions

项目摘要

Project Summary In melanoma and other cancers, the expansion of the local lymphatic network via expression of VEGF-C in the tumor microenvironment promotes metastasis and is widely correlated with poor prognosis. We and others have shown that VEGF-C-activated lymphatic vessels play important immune suppressive roles in the tumor microenvironment. Paradoxically, we have observed that in mouse melanoma models, lymphangiogenic tu- mors were more responsive to immunotherapy, including in adoptive T cell therapy, dendritic cell vaccines, and protein vaccination. Here we propose a research program that explores this other side of tumor lymphangio- genesis, and suggest a novel hypothesis that while VEGF-C in the tumor microenvironment can induce in- flammation and immune suppression, it also enhances the infiltration of naïve T cell infiltration, at least in part by upregulating the lymphoid homing chemokine CCL21. This enhanced infiltration, in turn, can prime the tu- mor for enhanced responsiveness to immunotherapy. Three aims are proposed to explore (i) validation and mechanistic underpinnings in mouse models, (ii) relevance to human melanoma, and (iii) translational applica- tion.

项目总结