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: 10211290
• 负责人: Hasan Korkaya
• 金额: $ 35.23万
• 依托单位: AUGUSTA 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/10211290
• 关键词: Aggressive behavior; Antitumor Response; Binding; Biological Assay; CSF3 gene; Cell Death; Cells; Clinical; Clinical Data; Clinical Research; Communication; Cytokine Activation; Cytoprotection; Cytotoxic T-Lymphocytes; Cytotoxic agent; Data; Development; Disease; Disease Progression; Effectiveness; Epithelial; Evolution; Generations; Goals; Heat-Shock Proteins 70; IL6 gene; Immune; Immune checkpoint inhibitor; Immune system; Immunosuppression; Immunotherapy; In Vitro; Inflammatory; Knockout Mice; Literature; Longevity; 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-Derived; Tumor-Infiltrating Lymphocytes; Woman; Work; anti-tumor immune response; base; cancer cell; cancer stem cell; cancer subtypes; chemotherapy; clinically relevant; cytokine; epithelial to mesenchymal transition; granulocyte; immune checkpoint blockade; improved; inhibitor/antagonist; macrophage; malignant breast neoplasm; metastatic process; mouse model; neoplastic cell; neutrophil; 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.

不同的上皮向间充质转化(EMT)表型与肿瘤干细胞的关系已被广泛接受 三阴性乳腺的细胞(CSC)特性及免疫抑制肿瘤微环境(TME) 癌症(TNBC)亚型是这种疾病侵袭性行为的原因。尽管肿瘤水平的增加- TNBC中的浸润性淋巴细胞(TIL)预示着更好的临床结果，这些患者中的大多数表现为 由于免疫抑制的TME而导致的进行性疾病。尽管TME/转移前病变的临床意义 疾病进展中的生态位已经被很好地认识到，调节这些的分子机制 这一过程仍然难以捉摸。临床前和临床数据提供了令人信服的证据，证明髓系免疫细胞 起源(巨噬细胞、中性粒细胞、MDSCs)是TME的主要成分，预示着预后不良 以及治疗抵抗力。因此，需要进一步的研究来了解潜在的分子 免疫抑制TME/转移前生态位的形成机制及其在疾病进展中的作用 和治疗抵抗。我们在这项应用中的主要目标是：确定压力是如何诱导的 HSP70调节两个基本过程：i)通过诱导 上皮间充质转化(EMT)和肿瘤干细胞(CSC)表型和II)产生许可 通过免疫抑制髓系细胞的调节来调节微环境。我们的中心假设是A20 TNBCs中诱导的HSP70在诱导EMT表型的同时保护肿瘤细胞免受细胞毒细胞死亡 炎性细胞因子，进而促进免疫抑制的MDSCs的积累。因此， 靶向HSP70将对肿瘤和MDSCs具有双重活性。我们的理论基础是，确定 使肿瘤细胞对细胞毒药物增敏同时逆转免疫抑制的分子机制(S) 提高目前可用的治疗方法的有效性。我们之前证明了肿瘤的生长 转移部位依赖于粒细胞MDSCs和抗肿瘤反应的抑制，因此 阻断HSP70与标准护理和/或检查点抑制剂联合使用可能具有重要的临床意义 利益。基于这些概念，我们建议通过调查以下具体目标来检验我们的假设： Aim 1将验证A20/HSP70信号轴相互作用为肿瘤细胞提供细胞保护的假设 通过在TNBC亚型中诱导EMT/CSC表型。目标2将检验热休克蛋白70调节的假设 免疫抑制MDSC的诱导和活性。目标3将确定分子机制和功能 HSP70在TME发生和转移前生态位中的重要性在我们的提案完成后，我们 希望阐明HSP70细胞保护肿瘤细胞免受细胞毒剂的分子机制 诱导EMT/CSC表型的同时调节免疫抑制的MDSCs应答肿瘤分泌 促进肿瘤进展的细胞因子。它还将确定阻断HSP70是否会增强 化疗和/或免疫治疗在代表TNBC亚型的同基因小鼠模型中的疗效。