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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

基本信息

批准号：
9757722
负责人：
Sonia Sharma
金额：
$ 39.27万
依托单位：
LA JOLLA INSTITUTE FOR IMMUNOLOGY
依托单位国家：
美国
项目类别：
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/9757722
关键词：
Adaptor Signaling Protein Adoptive Transfer Animal Cancer Model Antigens Antitumor Response 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 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 Tumor-infiltrating immune cells Vascular Endothelial Cell 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

项目摘要

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(申请人提供)：免疫学家长期以来一直相信免疫系统具有特异性靶向肿瘤细胞的能力，然而，直到最近十年，人们才清楚地看到，i)免疫系统识别癌症特异性抗原并清除肿瘤，ii)肿瘤抵抗免疫监视，iii)进行肿瘤特异性免疫很可能成为有效癌症治疗的关键组成部分。自然或自发的免疫原性、白细胞浸润性肿瘤显示出独特的分子特征，标志着天然免疫反应的激活，这形成了免疫系统对成熟、主动的癌症监测。癌症免疫治疗中增强先天抗肿瘤反应的努力主要集中在树突状细胞和巨噬细胞上，它们被认为是先天免疫的主要效应者。然而，我们实验室的初步数据表明，血管内皮细胞(VECs)通过结合免疫刺激的无细胞DNA并对其做出反应来启动显著强大的先天免疫反应，这与它们作为血液哨兵的角色很好地一致。尽管越来越多的人认识到血管内皮细胞是微生物感染过程中真正的先天效应细胞，但对血管内皮细胞如何参与先天抗肿瘤反应、正常内皮细胞的先天反应如何与肿瘤来源的内皮细胞进行比较以及先天内皮细胞反应对肿瘤微环境炎症环境的影响还知之甚少。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，肿瘤来源的血管内皮细胞代表了一种潜在的未开发的和丰富的天然效应来源，用于癌症免疫监测。将利用内皮-肿瘤细胞共培养、RNA测序、RNAi/CRISPR介导的基因缺失、癌症动物模型和人类肺癌生物样本来研究将内皮天然免疫作为癌症免疫治疗的新靶点的先前未被探索和高度创新的想法。这项建议利用了不同的技能和专业知识，专注于了解内皮固有免疫信号及其在癌症免疫监测中的作用。它汇集了首席研究员索尼娅·夏尔马博士，她是一名女性早期研究员，在天然免疫、免疫细胞信号转导、细胞钙信号转导和高通量RNAi或基于CRISPR/CAS9的基因组方法等领域有公认的高影响观察记录，以及在生物统计/信息学、癌症动物模型和人类肺癌生物样本方面的专业知识。