Dual function of HSP70 in cytoprotection of tumor cells and generation of permissive microenvironment

HSP70 在肿瘤细胞的细胞保护和产生许可微环境中的双重功能

• 批准号: 10897559
• 负责人: Hasan Korkaya
• 金额: $ 23.04万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10897559
• 关键词: Aggressive behavior; Antitumor Response; Binding; Biological Assay; CSF3 gene; Cell Death; Cell Death Induction; Cells; Clinical; Clinical Data; Clinical Research; Communication; Cytokine Activation; Cytoprotection; Cytotoxic T-Lymphocytes; Cytotoxic agent; Data; Development; Disease; Disease Progression; Effectiveness; Epithelium; Generations; Goals; Heat-Shock Proteins 70; IL6 gene; Immune; Immune checkpoint inhibitor; Immune system; Immunosuppression; Immunotherapy; In Vitro; Inflammatory; Knockout Mice; Literature; Longevity; Macrophage; Mediating; Mesenchymal; Metastatic breast cancer; Molecular; Molecular Target; Mus; Myelogenous; Myeloid Cells; Myeloid-derived suppressor cells; Natural Killer Cells; Neoplasm Metastasis; Outcome; Pathway interactions; Patients; Phenotype; Play; Process; Production; Prognosis; Progressive Disease; Property; Publishing; Research; Role; Sampling; Signal Transduction; Site; Stress; Stromal Cells; Testing; Therapeutic; Toll-like receptors; Transactivation; Tumor Promotion; Tumor-Derived; Tumor-Infiltrating Lymphocytes; Woman; Work; anti-tumor immune response; cancer cell; cancer stem cell; cancer subtypes; chemotherapy; clinically relevant; cytokine; epithelial to mesenchymal transition; granulocyte; immune checkpoint blockade; improved; inhibitor; malignant breast neoplasm; metastatic process; mouse model; neoplastic cell; neutrophil; permissiveness; pre-clinical; resistance mechanism; response; standard of care; therapeutic evaluation; therapy resistant; treatment response; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor microenvironment; tumor progression; tumor-immune system interactions

It has been widely accepted that distinct epithelial to mesenchymal transition (EMT) phenotype and cancer stem cell (CSC) properties as well as the immunosuppressive tumor microenvironment (TME) in triple negative breast cancer (TNBC) subtype account for the aggressive behavior of this disease. Although increased levels of tumor- infiltrating lymphocytes (TILs) in TNBC predicted better clinical outcome, the majority of these patients display progressive disease due to the immunosuppressive TME. Although the clinical relevance of TME/pre-metastatic niche in disease progression has been well recognized, the molecular mechanisms that regulate these processes remain elusive. Preclinical and clinical data provide compelling evidence that immune cells of myeloid origin (macrophages, neutrophils, MDSCs) are major components of the TME and predictive of poor prognosis as well as therapeutic resistance. Therefore, further research is required to understand the underlying molecular mechanism of formation of immunosuppressive TME/pre-metastatic niche and its role in disease progression and therapeutic resistance. Our primary objectives in this application are; to determine how stress-induced HSP70 regulates two fundamental processes; i) protecting tumor cells from cytotoxic cell death by inducing an epithelial mesenchymal transition (EMT) and cancer stem cell (CSC) phenotype and ii) generating a permissive microenvironment via the modulation of immunosuppressive myeloid cells. Our central hypothesis is that A20 induced HSP70 in TNBCs protects tumor cells from cytotoxic cell death while inducing an EMT phenotype and inflammatory cytokines which in turn promote the accumulation of immunosuppressive MDSCs. Therefore, targeting HSP70 will have a dual activity on tumors and MDSCs. Our rationale is that the identification of molecular mechanism(s) that sensitize tumor cells to cytotoxic agents while reversing immunosuppression will improve the effectiveness of currently available therapeutics. We previously demonstrated that growth of tumors at metastatic sites is dependent of granulocytic MDSCs and suppression of anti-tumor responses and thus blocking HSP70 in combination with standard of care and/or checkpoint inhibitors could have significant clinical benefit. Based on these concepts we propose to test our hypothesis by investigating the following specific aims: Aim 1 will test the hypothesis that a reciprocal A20/HSP70 signaling axis provides cytoprotection to tumor cells by inducing EMT/CSC phenotype in TNBC subtype. Aim 2 will test the hypothesis that HSP70 regulates immunosuppressive MDSC induction and acitivity. Aim 3 will determine the molecular mechanism and functional importance of HSP70 in generation of TME and pre-metastatic niche. At the completion of our proposal, we expect to elucidate the molecular mechanism by which HSP70 cytoprotects tumor cells from cytotoxic agents by inducing EMT/CSC phenotype while regulating the immunosuppressive MDSCs in response tumor secreted cytokines facilitating the tumor progression. It will also determine whether blocking HSP70 potentiates the efficacy of the chemotherapies and/or immunotherapy in syngeneic mouse models representing TNBC subtype.

不同的上皮细胞向间充质细胞转化（EMT）表型与肿瘤的发生有密切关系