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: 8385728
• 负责人: Nathalie Scholler
• 金额: $ 20.88万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 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 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8385728
• 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; Screening procedure; 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; standard care; success; therapeutic target; toll-like receptor 4; tumor; tumor growth; tumor immunology

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. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because it proposes to identify constitutive molecular variants of toll-like receptors (TLR variants) that can be activated by tumor cell debris (DAMPs) generated by chemotherapeutic drugs, leading to chronic inflammation in the tumor microenvironment, tumor growth and chemoresistance. The project includes 1/ in vitro functional studies and TLR sequencing of immune cells from healthy donors to link TLR variants with DAMP-dependant functional polymorphisms, and 2/ [deletion of previous aim#2] identifications of TLR single-nucleotide polymorphisms linked to ovarian cancer chemoresistance using The Cancer Genome Atlas (NCI) bank. The proposed research is relevant to NIH's mission to developing fundamental knowledge that can translate into screening tests enabling cancer early detection and personalized anti-cancer therapy.

描述（申请人提供）：设计新的卵巢癌治疗策略需要了解化疗耐药分子机制。MyD88在癌症中起着关键作用。MyD88敲除小鼠（MyD88-/-）对多种致癌物诱导的癌症具有抗性，MyD88的表达与卵巢癌患者的负生存率相关。除TLR3外，所有toll样受体（tlr）都通过MyD88发出信号，从而触发促炎细胞因子的产生。tlr是模式识别受体（PRRs），可识别保守的病原体相关分子模式（PAMPs）和内源性危险信号（DAMPs）。TLR配体已在临床中作为免疫刺激分子与抗癌治疗相结合，但它们可能引起有益或有害的影响。解释这些矛盾结果的原因包括卵巢癌主要化疗药物紫杉醇与TLR4的结合，以及TLR4变异与癌症风险相关。目前尚未发现TLR变异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/或克服癌症化疗耐药性。本研究的目的是鉴定肿瘤浸润性免疫细胞表达的TLR变异，这些变异在紫杉醇和/或肿瘤释放的DAMPs参与后可以介导损伤连锁反应。我们的中心假设是，化疗可以通过PAMPS和肿瘤释放的DAMPs参与TLR变体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，这取决于患者的TLR变体。其基本原理是发现TLR变异促进肿瘤的发生