Targeting tumor endothelium for cancer surveillance and immunotherapy

靶向肿瘤内皮细胞进行癌症监测和免疫治疗

• 批准号: 9329380
• 负责人: Sonia Sharma
• 金额: $ 40.49万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-03 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9329380
• 关键词: Adaptor Signaling Protein; Adoptive Transfer; Animal Cancer Model; Antigens; Biometry; Blood; Blood Circulation; Bone Marrow; CD8-Positive T-Lymphocytes; CRISPR/Cas technology; Cancer Patient; Cell Separation; Cells; Chimera organism; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Coculture Techniques; DNA; Data; Dendritic Cells; Effector Cell; Endothelium; Environment; Evaluation; Female; Gene Deletion; Genomic approach; Government; Human; Immune; Immune Evasion; Immune response; Immune signaling; Immune system; Immunity; Immunologic Surveillance; Immunologist; Immunotherapeutic agent; Immunotherapy; In Vitro; Infection; Infiltration; Inflammatory; Informatics; Innate Immune Response; Innate Immune System; Knock-out; Laboratories; Leukocytes; Ligands; Link; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Molecular Profiling; Natural Immunity; Pathway interactions; Patient-Focused Outcomes; Persons; Play; RNA Interference; Research Personnel; Resources; Role; Sampling; Sentinel; Shapes; Signal Pathway; Signal Transduction; Source; Sting Injury; Techniques; Tumor Immunity; Tumor-Derived; Vascular Endothelial Cell; Vascular Endothelium; Work; base; cancer cell; cancer immunotherapy; cancer therapy; cell free DNA; experimental study; extracellular; functional genomics; immune activation; immunogenic; immunogenicity; in vivo; innovation; macrophage; microbial; neoplastic cell; next generation; novel; public health relevance; response; skills; transcriptome sequencing; tumor; tumor DNA; tumor growth; tumor microenvironment; whole genome

 DESCRIPTION (provided by applicant): Immunologists have long believed in the power of the immune system to specifically target neoplastic cells, however, only in the last decade has it become clear that i) the immune system recognizes cancer-specific antigens and eliminate tumors, ii) tumors resist immune surveillance, and iii) engaging tumor-specific immunity is likely to become a key component of effective cancer therapies. Naturally or spontaneously immunogenic, leukocyte-infiltrated tumors display the distinctive molecular signatures signifying activation of the innate immune response, which shapes mature, active cancer surveillance by the immune system. Efforts to boost innate anti-tumor responses for cancer immunotherapy primarily focus on dendritic cells and macrophages, considered to be principal effectors of innate immunity. However, preliminary data from our laboratory demonstrates that vascular endothelial cells (vECs) mount remarkably potent innate immune responses by taking up and responding to immuno-stimulatory, cell-free DNA, which is well in accordance with their role as sentinels of the blood. Despite an increasingly accepted appreciation for vECs as bona fide innate effector cells during microbial infections, little is known about how innate anti-tumor responses are engaged in vECs, how innate responses of normal endothelium compare with tumor-derived endothelium, and what is the contribution of innate endothelial responses to the inflammatory landscape of the tumor microenvironment. Our hypothesis asserts that the innate responses of vECs to tumor-derived DNA are suppressed by the tumor microenvironment. Nonetheless, tumor-derived vECs represent a potentially untapped and rich source of innate effectors for cancer immune surveillance. The previously unexplored and highly innovative idea of examining endothelial innate immunity as a novel target for cancer immunotherapy will be investigated using endothelial-tumor cell co-cultures, RNA-sequencing, RNAi/CRISPR-mediated gene deletion, animal models of cancer and human lung tumor biosamples. This proposal leverages diverse skills and expertise focused on understanding endothelial innate immune signaling and its role in cancer immune surveillance. It brings together the principle investigator Dr. Sonia Sharma, a female early stage investigator with an established record of high impact observations in the fields of innate immunity, signal transduction in immune cells, cellular Ca2+ signaling and high throughput RNAi or CRISPR/Cas9-based genomic approaches, with key collaborators with expertise in bio-statistics/informatics, animal models of cancer and human lung tumor biosamples.

 描述（由申请人提供）：免疫学家长期以来一直相信免疫系统特异性靶向肿瘤细胞的能力，然而，仅在过去十年中才清楚地认识到i）免疫系统识别癌症特异性抗原并消除肿瘤，ii）肿瘤抵抗免疫监视，以及iii）参与肿瘤特异性免疫可能成为有效癌症治疗的关键组成部分。天然或自发免疫原性的白细胞浸润肿瘤显示出独特的分子特征，表明先天免疫应答的激活，这形成了免疫系统对成熟、活跃的癌症的监视。增强用于癌症免疫治疗的先天性抗肿瘤应答的努力主要集中在树突状细胞和巨噬细胞，它们被认为是先天免疫的主要效应物。然而，来自我们实验室的初步数据表明，血管内皮细胞（vEC）通过摄取和响应免疫刺激性的无细胞DNA而产生非常有效的先天免疫应答，这与它们作为血液哨兵的作用完全一致。尽管在微生物感染过程中，越来越多的人接受vEC作为真正的先天效应细胞，但对vEC如何参与先天抗肿瘤反应，正常内皮的先天反应如何与肿瘤来源的内皮进行比较，以及先天内皮反应对肿瘤微环境的炎症景观的贡献知之甚少。我们的假设认为，血管内皮细胞对肿瘤来源的DNA的先天反应受到肿瘤微环境的抑制。尽管如此，肿瘤来源的vEC代表了癌症免疫监视的先天效应物的潜在未开发和丰富的来源。将使用内皮-肿瘤细胞共培养物、RNA测序、RNAi/CRISPR介导的基因缺失、癌症动物模型和人肺肿瘤生物样品来研究以前未探索和高度创新的检查内皮先天免疫作为癌症免疫治疗新靶点的想法。该提案利用了各种技能和专业知识，专注于了解内皮先天免疫信号及其在癌症免疫监视中的作用。它汇集了主要研究者Sonia Sharma博士，一位女性早期研究者，在先天免疫，免疫细胞信号转导，细胞Ca 2+信号传导和高通量RNAi或CRISPR/Cas9基因组方法领域具有高影响力的观察记录，与生物统计学/信息学，癌症动物模型和人类肺肿瘤生物样品方面的专业知识的关键合作者。