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Boosting Antitumor Immunity by Blocking Both Tumor and Adipose DDR1

通过阻断肿瘤和脂肪 DDR1 来增强抗肿瘤免疫力

基本信息

批准号：
9980667
负责人：
Rong Li
金额：
$ 47.69万
依托单位：
GEORGE WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-05 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9980667
关键词：
Address Adipocytes Adipose tissue Adoptive Transfer Antitumor Response Attenuated Binding Biological Assay Breast Cancer Model Breast Cancer Patient Cancer Biology Cell Compartmentation Cell physiology Cells Clinical Clinical Oncology Coculture Techniques Collagen Collagen Fibril Collagen Receptors Communication Complex Data Development Diet Extracellular Domain Future Human Immune Immunocompetent Immunologics Immunooncology Immunophenotyping Immunosuppression Immunotherapeutic agent Immunotherapy In Vitro In complete remission Infiltration Integration Host Factors Knock-out Knockout Mice Knowledge Ligands Literature Mammary Neoplasms Mediating Molecular Mus New Agents Non obese Obesity Obesity associated cancer Patient-Focused Outcomes Patients Phosphotransferases Positioning Attribute Production Protein Tyrosine Kinase Receptor Protein-Tyrosine Kinases Reporting Resistance Role Sampling Signal Transduction Stromal Neoplasm Technology Testing Time Tissues Tumor Immunity Woman anti-tumor immune response attenuation base cancer immunotherapy cell type comorbidity cytokine discoidin domain receptor 1 experimental study immunoregulation malignant breast neoplasm migration mouse genetics mouse model multidisciplinary neoplastic cell novel patient subsets response targeted treatment tool tumor tumor growth tumor immunology tumor microenvironment tumor progression

项目摘要

ABSTRACT Despite significant clinical breakthroughs in anticancer immunotherapy, the efficacy of current immunotherapies in breast cancer is modest. Only a small fraction of breast cancer patients have a clinical response; complete responses to these agents are exceedingly rare. The underlying mechanisms of tissue- specific immune regulation in breast cancer remains to be elucidated. Furthermore, how comorbidities such as obesity influence antitumor immunity in breast cancer is even less understood. Discoidin domain receptor 1 (DDR1) is a collagen receptor with an intrinsic tyrosine kinase activity. High DDR1 expression in breast cancer is associated with poor patient outcomes and attenuated antitumor immunity. We found complex tumor-promoting actions for both tumor and adipose DDR1 in the breast tumor microenvironment. Tumor DDR1 suppresses antitumor immunity, whereas adipose DDR1 is required for diet- induced obesity, tumor-promoting cytokine production, and immune modulation. Our preliminary data further indicate that the shed extracellular domain of DDR1 alone is sufficient for its functions in tumor and adipose cells, which has not previously been reported. We therefore hypothesize that DDR1 in the breast tumor microenvironment promotes tumor progression by dampening antitumor immunity, enabling adiposity, and abetting immune-adipose cell-tumor crosstalk. We predict that blocking kinase-independent DDR1 signals can boost antitumor immunity and response to anticancer immunotherapies, especially in patients with obesity. To test this hypothesis, in this R01 application, we will determine how tumor DDR1 suppresses antitumor immunity (Aim 1), how adipose DDR1 contributes to obesity-associated cancer progression (Aim 2), and how DDR1 carries out its immune-suppressive functions independent of its kinase activity (Aim 3). With combined expertise in cancer biology, tumor immunology, and clinical oncology, our multidisciplinary team is well positioned to validate our novel hypothesis. The fact that DDR1 has distinct functions in different cell compartments of the breast tumor microenvironment underscores the complexity of tumor-stromal interactions. By investigating tumor and adipose DDR1 in an integrative and comprehensive manner as proposed here, we will fill major gaps of knowledge about tumor-initiated immune suppression and obesity-associated comorbid effects. Given the adipocyte-rich tumor microenvironment in breast cancer and the growing numbers of patients with obesity and breast cancer, our proposed studies address an unmet clinical need and promise to inform the development of new strategies to enhance antitumor immunity for breast cancer patients, especially for those with obesity. !

摘要