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

项目3摘要 病毒致癌占总癌症的20%。尤其是KSHV和HPV是 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需要一种 辅助因子发展成肿瘤病变。通常，艾滋病毒合并感染是最重要的 与KSHV和HPV相关，因为它会减弱免疫反应。 活性抗逆转录病毒 治疗(HAART)已经成为一种有效的治疗方法，但有时患者会进展并需要 附加治疗 。Galectin-1(Gal1)，一种具有免疫抑制作用的糖链结合蛋白 通过诱导活化的T细胞的凋亡来调节肿瘤微环境， 推介 IL-27-Foxp3+Treg.最近，我们有 致耐受树突状细胞及其扩增 证明VEGFR2上的Gal1-N-聚糖与肿瘤缺氧和异常血管生成有关 并在抗血管内皮生长因子难治性肿瘤中保留血管形成，促进肿瘤生长和 转移。这些数据表明，靶向Gal1-N-多糖相互作用可能会克服 通过促进代偿性血管生成和通过 增强免疫反应。糖糖的特异性变化和Gal1的上调 被感染的病毒致癌细胞似乎是新一代肿瘤发展的关键 肉瘤、卡波西肿瘤和人乳头瘤病毒相关恶性肿瘤的治疗。抗Gal1单抗 可以重新教育免疫系统，改进实际的治疗方法。在这个项目中，我们建议 使用跨学科的方法来探索Gal1-N-葡聚糖轴作为潜在的 微调关键信号在病毒相关肿瘤发病中的作用 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依赖的异常信号和增强抗肿瘤作用 豁免权。

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.