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的分子机制。MyD88在癌症中起着关键作用。MyD88基因敲除小鼠(MyD88-/-)对多种致癌物诱导的癌症具有抵抗力，MyD88的表达与卵巢癌患者的阴性生存相关。除TLR3外，所有的Toll样受体(TLRs)都通过MyD88发出信号，从而触发促炎细胞因子的产生。TLRs是一种模式识别受体，既能识别保守的病原体相关分子模式(PAMPs)，又能识别内源性危险信号(DAMP)。TLR配体已经在临床上作为免疫刺激分子与抗癌治疗相结合使用，但它们可以引起有益的或有害的影响。解释这些相互矛盾的结果的原因包括用于治疗卵巢癌的主要化疗药物之一紫杉醇与TLR4的结合，以及TLR4变异的存在与癌症风险有关。到目前为止，还没有人描述TLR变异体与卵巢癌之间的联系。我们的长期目标是开发个性化的治疗策略，以预防和/或克服癌症的化疗耐药性。本研究的目的是确定肿瘤浸润性免疫细胞表达的TLR变异体，这些变异体在紫杉醇和/或肿瘤释放的阻滞剂作用后能够介导损伤链式反应。我们的中心假设是，化疗可以通过PAMP和肿瘤释放的DAMP与TLR变体的接触来重新编程肿瘤浸润性免疫细胞，导致肿瘤排斥或慢性炎症、损伤连锁反应和化疗耐药，具体取决于患者的TLR变体。其基本原理是识别促进肿瘤的TLR变异体 化疗反应中的排斥反应或慢性炎症将允许设计个性化的治疗方案，并极大地改善患者的预后。这一假设将通过追求两个特定的目标来验证：1)通过筛选外周血淋巴细胞对紫杉醇和肿瘤释放的阻滞剂的功能多态性来识别容易发生损伤链式反应的捐赠者。来自200名健康捐献者的免疫细胞的表型和功能变化将在紫杉醇存在的情况下与化疗敏感和耐药的卵巢肿瘤细胞共同培养后进行表征；2)[删除先前的目的2]研究浆液性卵巢癌标本中TLR SNP的相关性，这与与化疗反应和临床结果相关的临床数据有关。这种方法是创新的，因为它建议检查卵巢癌的化疗耐药性，这是紫杉醇和肿瘤释放的DAMP与免疫细胞上的结构性TLR变体特异性结合的结果。这项研究意义重大，因为如果成功，它将使针对DAMPS的个性化治疗药物的设计成为可能，以阻止与TLR变体的异常结合，从而阻止慢性炎症，从而使患者对化疗药物产生反应。