Research Project 3 Galectin-1-glycan interactions: Novel regulatory checkpoints linking immunosuppression and angiogenesis in virally induced cancers

研究项目 3 Galectin-1-聚糖相互作用：在病毒诱导的癌症中将免疫抑制和血管生成联系起来的新型调节检查点

• 批准号: 10488072
• 负责人: Gabriel Rabinovich
• 金额: $ 7.35万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-20 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10488072
• 关键词: AIDS related cancer; AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Address; Advanced Malignant Neoplasm; Affect; Amplifiers; Animal Model; Anus; Apoptosis; Argentina; Attenuated; Binding; Binding Proteins; Biological; Blood Vessels; Carcinogenesis Mechanism; Cell Cycle Regulation; Cells; Cervical; Characteristics; Clinical; Collaborations; Complex; Data; Dendritic Cells; Development; Diagnostic; Epithelial; Epithelial Cells; Epithelial Neoplasms; Event; FOXP3 gene; Galactose Binding Lectin; Galectin 1; Galectin 3; Generations; Goals; HIV; HPV-High Risk; Head and Neck Neoplasms; Highly Active Antiretroviral Therapy; Human; Human Herpesvirus 8; Human Papilloma Virus-Related Malignant Neoplasm; Human Papillomavirus; Human papilloma virus infection; Human papillomavirus 16; Immune; Immune response; Immune system; Immunity; Immunocompetent; Immunologic Surveillance; Immunophenotyping; Immunosuppression; Immunotherapy; Infection; Inflammation; Integration Host Factors; Interruption; KDR gene; Kaposi Sarcoma; Lectin; Lectin Receptors; Lesion; Ligands; Link; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Mediating; Modality; Modeling; Molecular; Monoclonal Antibodies; Mus; Nature; Neoplasm Metastasis; Neoplasms; Oncogenic; Oncogenic Viruses; Pathogenesis; Pathogenicity; Patients; Phenotype; Platelet-Derived Growth Factor alpha Receptor; Polysaccharides; Population; Prevalence; Process; Refractory; Regulation; Regulatory T-Lymphocyte; Research Project Grants; Research Training; Resistance; Risk Factors; Role; Sampling; Signal Pathway; Signal Transduction; T-Lymphocyte; Tetracyclines; Therapeutic; Time; Transgenic Mice; Tumor Angiogenesis; Tumor Immunity; Up-Regulation; Vascular Endothelial Growth Factors; Vascularization; Viral; Viral Cancer; Viral Pathogenesis; Virus; angiogenesis; antiretroviral therapy; base; bevacizumab; cancer therapy; carcinogenesis; co-infection; cofactor; diagnostic biomarker; effective therapy; exhaustion; glycosylation; high risk; immunoregulation; improved; interdisciplinary approach; men who have sex with men; neoplastic; neutralizing monoclonal antibodies; novel; novel therapeutics; preservation; progenitor; repository; response; sarcoma; segregation; success; targeted treatment; therapeutic target; treatment response; tumor; tumor growth; tumor hypoxia; tumor microenvironment; tumorigenesis; virus related cancer

Project 3 Abstract Viral oncogenesis is responsible of 20% of total cancer. In particular, KSHV and HPV are the most common oncogenic viruses infecting millions of patients per year. Although the efficiency of these viruses to alter cell cycle regulation and manipulate cell signal pathways they need a co-cofactor to develop neoplastic lesions. Frequently, HIV co-infection is the most important association with KSHV and HPV because attenuates immune response. Active antiretroviral treatment (HAART) has become an effective therapy but at time patients progress and require additional treatments . Galectin-1 (Gal1), a glycan binding protein with immunosuppressive effects modulates tumor microenvironments by inducing apoptosis of activated T cells, promoting IL-27- Foxp3+ Tregs. Recently, we have tolerogenic dendritic cells and expanding demonstrated that Gal1-N-glycans on VEGFR2 links tumor hypoxia to aberrant angiogenesis and preserves vascularization in anti-VEGF refractory tumors facilitating tumor growth and metastasis. These data, suggest that targeting Gal1-N-glycan interactions may overcome resistance to anti-cancer therapies by promoting compensatory angiogenesis and by potentiating immune responses. Specific changes in the glycome and up-regulation of Gal1 in infected viral oncogenic-cells seems to be the key for the development of a new generation of therapies for sarcoma kaposi tumors and HPV-associated malignancies. Anti-Gal1 mAbs could re-educate immune system improving actual therapies. In this project, we propose to use an interdisciplinary approach to explore the Gal1-N-glycan axis as a potential player in pathogenesis of viral-associated tumors by fine tuning critical signaling pathways and promoting oncogenic inflammation with the ultimate goal to improve a new generation diagnostic and therapeutic strategies aimed at limiting tumor growth by suppressing PDGFRA-dependent aberrant signaling and potentiating antitumor immunity.

项目3 病毒性肿瘤发生占总癌症的20%。特别是KSHV和HPV， 最常见的致癌病毒每年感染数百万患者。 虽然效率 这些病毒改变细胞周期调节和操纵细胞信号通路，他们需要一个 辅辅因子发展成肿瘤性病变。通常，艾滋病毒合并感染是最重要的 与KSHV和HPV相关，因为减弱免疫反应。 活性抗逆转录病毒 高效抗逆转录病毒治疗（HAART）已成为一种有效的治疗方法，但有时患者进展并需要 额外治疗 .半乳糖凝集素-1（Gal 1），一种具有免疫抑制作用的聚糖结合蛋白 作用通过诱导活化T细胞的凋亡来调节肿瘤微环境， 促进 IL-27-Foxp 3 + T细胞。最近我们 致耐受性树突状细胞和扩增 表明VEGFR 2上的Gal 1-N-聚糖将肿瘤缺氧与异常血管生成联系起来 并在抗VEGF难治性肿瘤中保持血管形成，促进肿瘤生长， 转移这些数据表明，靶向Gal 1-N-聚糖相互作用可以克服 通过促进代偿性血管生成和通过 增强免疫反应糖组的特异性变化和Gal 1的上调 感染的病毒致癌细胞似乎是新一代肿瘤细胞发展的关键。 卡波西肉瘤肿瘤和HPV相关恶性肿瘤的治疗。抗Gal 1 mAb 可以重新教育免疫系统，改善实际的治疗方法。在这个项目中，我们建议 使用跨学科的方法来探索Gal 1-N-聚糖轴作为一种潜在的 通过微调关键信号在病毒相关肿瘤发病机制中的作用 途径和促进致癌性炎症，最终目标是改善 旨在限制肿瘤生长的新一代诊断和治疗策略 通过抑制PDGFRA依赖性异常信号传导和增强抗肿瘤活性， 免疫力