Targeting exosomal PDL1 to improve immunotherapy

靶向外泌体 PDL1 改善免疫​​治疗

• 批准号: 10268744
• 负责人: WEI GUO
• 金额: $ 43.44万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-03 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10268744
• 关键词: Academia; Biological Assay; Biological Markers; Blood; Blood Circulation; CD8-Positive T-Lymphocytes; Caliber; Cell physiology; Cells; Clinical; Coculture Techniques; Combined Modality Therapy; Data; Development; Dimensions; Encapsulated; Foundations; Future; Goals; Immune checkpoint inhibitor; Immunologics; Immunosuppression; Immunotherapy; In Vitro; Individual; Industry; Infrastructure; Intervention; Knowledge; Lipids; Measurement; Measures; Mediating; Melanoma Cell; Metastatic Melanoma; Methods; Mus; Mutation; Myeloid Cells; Nature; Nivolumab; Outcome; Patient Selection; Patient-Focused Outcomes; Patients; Plasma; Play; Resistance; Role; Sampling; Sensitivity and Specificity; Series; Skin Cancer; System; T-Cell Proliferation; T-Lymphocyte; Testing; Therapeutic; Time; Toxic effect; Tumor Tissue; Tumor-associated macrophages; Tumor-infiltrating immune cells; Validation; Vesicle; Work; alternative treatment; anti-CTLA4 antibodies; anti-PD-1; anti-PD1 antibodies; anti-PD1 therapy; base; biomarker development; cancer type; checkpoint inhibition; clinical application; clinical decision-making; clinical development; clinical diagnostics; clinical practice; clinically relevant; exhaustion; exosome; experimental study; extracellular; humanized mouse; immune checkpoint; immune resistance; improved; improved outcome; interest; ipilimumab; liquid biopsy; macrophage; melanoma; mouse model; nano-exosomes; nanosized; neoplastic cell; novel; novel therapeutic intervention; patient derived xenograft model; patient response; patient stratification; pembrolizumab; personalized immunotherapy; predicting response; predictive marker; predictive test; prevent; programmed cell death ligand 1; programmed cell death protein 1; responders and non-responders; response; tool; treatment optimization; tumor; tumor growth; tumor progression

Project Summary - Project 1 Immune checkpoint inhibitors (ICI) such as anti-PD-1 antibodies have revolutionized anti-tumor therapy for many types of cancers including metastatic melanoma. However, the patient response rates are low. Combined therapies such as ipilimumab and nivolumab produce a higher response rate but are associated with significant toxicities. A major unmet need is to develop quantitative assays that stratify patients who will respond to anti- PD-1 therapy to avoid unnecessary toxicities, and direct non-responders to alternative treatments. Such a pre- treatment or early on-treatment predictor would provide decision-enabling information to clinicians to optimize the treatment of melanoma patients. While there is enormous interest and intensive efforts from both academia and industry to identify predictors to response to ICI, the current biomarkers are suboptimal and early on- treatment biomarkers are not available for any cancer types. Exosomes are nano-sized vesicles secreted by cells to the extracellular milieu. We found that metastatic melanoma cells secrete exosomes enriched with PD- L1, which suppress the function of CD8+ T cells in circulation and facilitate tumor growth. In patients’ plasma, the level of circulating exosomal PD-L1 (“exPD-L1”) and its change during the course of anti-PD-1 treatment are associated with the patient response to anti-PD-1 therapy (Chen et al., Nature 2018). Most recently, we found that tumor associated macrophages (TAM) also secrete exosomes that carry PD-L1 (“TAM-exPD-L1”), which can be selectively and quantitatively measured in patient blood. TAM exosomes effectively suppress the proliferation and function of CD8 T cells. The overarching goals of Project 1 are to develop a quantitative liquid biopsy-based tool that enables clinicians to predict the patient response to ICI-based therapies, and to understand the role of TAM-derived exosomes in immune suppression. In Aim 1, we will test the hypothesis that exPD-L1, and especially TAM-exPD-L1, individually or in combination, are effective predictors of patient response to ICI. We perform the assays using a large multi-institutional validation set of patient samples across different major therapeutic contexts, taking advantage of the unique infrastructure SPORE offers. In Aim 2, we will systematically investigate the pivotal roles of TAM-derived exosomes in immune suppression using melanoma-macrophage co-culture system, humanized mouse system, and exosomes purified directly from patient tumor tissues. Together, our work will establish exosomal PD-L1 as a rationale-based clinically relevant stratifier that warrants future development for clinical diagnostics. The proposed study will also unveil a role of TAM exosomes in immune suppression, which will not only advance our understanding of immune suppression at new dimensions, but also helps develop novel therapeutic approaches to improve the treatment of patients with melanoma.

项目摘要-项目1 免疫检查点抑制剂（ICI），如抗PD-1抗体，已经彻底改变了许多人的抗肿瘤治疗。 包括转移性黑色素瘤的癌症类型。然而，患者的反应率很低。组合 诸如易普利姆玛和纳武单抗的疗法产生更高的应答率， 毒性一个主要的未满足的需求是开发定量测定，该定量测定对将对抗-HCV应答的患者进行分层。 PD-1治疗以避免不必要的毒性，并将无应答者直接用于替代治疗。这样的预- 治疗或早期治疗预测将为临床医生提供决策支持信息，以优化 黑色素瘤患者的治疗。虽然学术界和学术界都有巨大的兴趣和密集的努力， 和行业来识别ICI反应的预测因素，目前的生物标志物是次优的，而且是在早期- 治疗生物标志物不可用于任何癌症类型。外泌体是纳米大小的囊泡， 细胞到细胞外环境。我们发现转移性黑色素瘤细胞分泌富含PD的外泌体- L1，其抑制循环中的CD 8 + T细胞的功能并促进肿瘤生长。在患者血浆中， 循环外泌体PD-L1（“exPD-L1”）的水平及其在抗PD-1治疗过程中的变化是 与患者对抗PD-1治疗的反应相关（Chen等人，Nature 2018）。最近，我们发现 肿瘤相关巨噬细胞（TAM）也分泌携带PD-L1的外泌体（“TAM-exPD-L1”）， 可以在患者血液中选择性地和定量地测量。TAM外泌体有效地抑制了 CD 8 T细胞的增殖和功能。项目1的总体目标是开发一种定量液体， 基于活检的工具，使临床医生能够预测患者对基于ICI的治疗的反应， 了解TAM衍生的外泌体在免疫抑制中的作用。在目标1中，我们将检验以下假设： exPD-L1，特别是TAM-exPD-L1，单独或组合，是患者预后的有效预测因子。 回答ICI。我们使用一个大型的多机构验证患者样本集进行检测， 不同的主要治疗环境，利用独特的基础设施孢子提供。在目标2中， 将系统地研究TAM衍生的外泌体在免疫抑制中的关键作用， 黑色素瘤-巨噬细胞共培养系统、人源化小鼠系统和直接从黑色素瘤-巨噬细胞共培养系统纯化的外泌体。 患者肿瘤组织。总之，我们的工作将建立外泌体PD-L1作为一个基于合理的临床相关的 分层器，保证了临床诊断的未来发展。拟议的研究还将揭示以下方面的作用： TAM外泌体在免疫抑制中的作用，这不仅将促进我们对免疫抑制的理解， 在新的层面，而且还有助于开发新的治疗方法，以改善患者的治疗 得了黑色素瘤