Linking tumor chemoresistance to TLR variants that mediate damage chain reaction

将肿瘤化疗耐药性与介导损伤链反应的 TLR 变异联系起来

• 批准号: 8507644
• 负责人: Nathalie Scholler
• 金额: $ 17.41万
• 依托单位: SRI INTERNATIONAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-09 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8507644
• 关键词: Adjuvant Therapy; Agonist; Angiogenic Factor; Antigen Presentation; Antineoplastic Agents; Apoptosis; B-Lymphocytes; Binding; CD4 Positive T Lymphocytes; Cancer Patient; Carboplatin; Carcinogens; Cell Death; Cells; Chronic; Cisplatin; Clinic; Clinical; Clinical Data; Coculture Techniques; Data; Dendritic Cells; Development; Drug resistance; Drug usage; Endocytosis; Event; Exhibits; Genetic Polymorphism; Goals; Immune; Immune response; Immune system; Immunotherapy; In Vitro; In complete remission; Inflammation; Knockout Mice; Knowledge; Ligands; Link; Lymphocyte; Malignant Neoplasms; Malignant neoplasm of ovary; Malignant neoplasm of prostate; Measures; Mediating; Microtubules; Mission; Molecular; Outcome; Paclitaxel; Patients; Pattern; Pattern recognition receptor; Peripheral; Peripheral Blood Lymphocyte; Phagocytes; Pharmaceutical Preparations; Phenotype; Platinum Compounds; Play; Production; Public Health; Reaction; Regulatory T-Lymphocyte; Relapse; Reporting; Research; Resistance; Role; S100 Proteins; S100A8 gene; Screening for cancer; Sequence Analysis; Serous; Signal Transduction; Single Nucleotide Polymorphism; Specimen; TLR3 gene; TLR4 gene; TLR7 gene; Testing; The Cancer Genome Atlas; Therapeutic; Tissues; Toll-like receptors; Translating; Variant; Work; anticancer treatment; base; cancer cell; cancer risk; cancer therapy; candidate marker; chemotherapy; cytokine; cytotoxicity; design; improved; innovation; macrophage; neoplastic; neoplastic cell; novel therapeutics; outcome forecast; ovarian neoplasm; pathogen; prevent; programs; response; screening; standard care; success; therapeutic target; toll-like receptor 4; tumor; tumor growth; tumor immunology; tumor microenvironment

DESCRIPTION (provided by applicant): Designing novel therapeutic strategies for ovarian cancer requires understanding chemoresistance molecular mechanisms. MyD88 plays a critical role in cancer. MyD88 knockout mice (MyD88-/-) are resistant to various carcinogen-induced cancers, and MyD88 expression correlates with negative survival of ovarian cancer patients. All Toll-like receptors (TLRs), but TLR3, signal through MyD88, which triggers the production of proinflammatory cytokines. TLRs are pattern recognition receptors (PRRs) that recognize both conserved pathogen-associated molecular patterns (PAMPs) and endogenous danger signals (DAMPs). TLR ligands have been used in clinics as immunostimulatory molecules in combination with anticancer treatments, but they can evoke either beneficial or deleterious effects. Reasons explaining these contradictory results include the binding of Paclitaxel, one of the main chemotherapeutic drugs used against ovarian cancer, to TLR4, and the existence of TLR4 variants linked with cancer risk. No link has been described as yet between TLR variants and ovarian cancer. Our long term goal is to develop personalized therapeutic strategies to prevent and/or overcome cancer chemoresistance. The objective of the studies herein is to identify TLR variants expressed by tumor-infiltrating immune cells that can mediate damage chain reaction after engagement by Paclitaxel and/or tumor-released DAMPs. Our central hypothesis is that chemotherapy can re-program tumor-infiltrating immune cells through the engagement of TLR variants by PAMPS and tumor-released DAMPs, leading to tumor rejection or chronic inflammation, damage chain reaction and chemoresistance, depending on the patients' TLR variants. The rationale is that the identification of TLR variants that promote tumor rejection or chronic inflammation in reaction to chemotherapy will permit to design personalized treatments and greatly improve patient prognosis. This hypothesis will be tested by pursuing two specific aims: 1) Identification of donors prone to damage chain reaction by screening peripheral blood lymphocytes for functional polymorphism in reaction to Paclitaxel and tumor-released DAMPs. Phenotype and functional changes of immune cells from 200 healthy donors will be characterized after co-culture with chemosensitive and chemoresistant ovarian tumor cells in presence of Paclitaxel; 2) [deletion of previous aim#2] Study of TLR snp association in serous ovarian cancer specimens that are linked to clinical data related to chemotherapy responses and clinical outcome. The approach is innovative because it proposes to examine ovarian cancer chemoresistance as a consequence of the specific engagement by Paclitaxel and tumor-released DAMPs to constitutive TLR variants on immune cells. This research is significant because, if successful, it will enable the design of personalized therapeutics targeted against DAMPs to block aberrant binding to TLR variants, thus chronic inflammation, therefore enabling patient responses to chemotherapeutic drugs.

描述（由申请人提供）：设计卵巢癌的新治疗策略需要了解化疗耐药分子机制。MyD 88在癌症中起着关键作用。MyD 88基因敲除小鼠（MyD 88-/-）对各种致癌物诱导的癌症具有抗性，MyD 88表达与卵巢癌患者的阴性存活相关。除了TLR 3之外，所有Toll样受体（TLR）都通过MyD 88发出信号，MyD 88触发促炎细胞因子的产生。TLR是模式识别受体（PRR），其识别保守的病原体相关分子模式（PAMP）和内源性危险信号（DAMP）。TLR配体已在临床上用作免疫刺激分子与抗癌治疗组合，但它们可引起有益或有害的作用。解释这些相互矛盾的结果的原因包括紫杉醇（用于治疗卵巢癌的主要化疗药物之一）与TLR 4的结合，以及与癌症风险相关的TLR 4变体的存在。TLR变异与卵巢癌之间还没有联系。我们的长期目标是开发个性化的治疗策略，以预防和/或克服癌症耐药性。本文研究的目的是鉴定由肿瘤浸润性免疫细胞表达的TLR变体，所述TLR变体可以在与紫杉醇和/或肿瘤释放的DAMP接合后介导损伤链反应。我们的中心假设是，化疗可以通过PAMPS和肿瘤释放的DAMP与TLR变体的接合来重新编程肿瘤浸润免疫细胞，导致肿瘤排斥或慢性炎症、损伤链反应和化疗耐药性，这取决于患者的TLR变体。基本原理是，识别促进肿瘤的TLR变体， 对化疗反应的排斥或慢性炎症将允许设计个性化治疗并大大改善患者预后。该假设将通过追求两个具体目标来检验：1）通过筛选外周血淋巴细胞对Paclitaxel和肿瘤释放的DAMP反应的功能多态性来鉴定易于发生损伤链反应的供体。来自200名健康供体的免疫细胞的表型和功能变化将在与化疗敏感性和化疗抗性卵巢肿瘤细胞在紫杉醇存在下共培养后表征; 2）[先前目的#2的删除]浆液性卵巢癌标本中TLR snp关联的研究，其与化疗反应和临床结果相关的临床数据相关。该方法是创新的，因为它提出检查卵巢癌化疗耐药性，作为Paclitaxel和肿瘤释放的DAMP对免疫细胞上的组成型TLR变体的特异性参与的结果。这项研究意义重大，因为如果成功，它将能够设计针对DAMP的个性化治疗方法，以阻断与TLR变体的异常结合，从而阻断慢性炎症，从而使患者对化疗药物产生反应。