Re-engineering differential regulation of ferroptosis in melanoma microenvironment

重新设计黑色素瘤微环境中铁死亡的差异调节

基本信息

批准号：
10735217
负责人：
Yuri Bunimovich
金额：
$ 69.09万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-12 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10735217
关键词：
Acceleration Affect Alcohols Apoptosis Blood specimen Carbon Nanotubes Cell Death Cell Differentiation process Cells Cessation of life Clinical Complementary therapies Complex Data Development Disabled Persons Engineering Genetic Genetic Models Glutathione Goals Human Immune Immune Tolerance Immune checkpoint inhibitor Immunosuppression Immunotherapy In Vitro Infiltration Ions Iron Lipid Peroxidation Lipid Peroxides Lipids MEKs Macrophage Malignant - descriptor Malignant Neoplasms Mass Spectrum Analysis Measures Mediating Melanins Melanogenesis Melanoma Cell Metastatic Skin Cancer Methods Modeling Modernization Mus Myelogenous Myeloid Cells Myeloid-derived suppressor cells Nanodelivery Neoplasm Transplantation Outcome Oxidation-Reduction Pathway interactions Patients Population Predisposition Process Publishing Refractory Regulation Resistance Sampling Signal Transduction System T-Lymphocyte Testing Therapeutic Tissue Sample Tumor Immunity Tumor Tissue Tumor-infiltrating immune cells alternative treatment analytical tool anti-tumor immune response cancer cell cancer therapy cell type checkpoint therapy clinically relevant cytotoxic cytotoxicity graphene imaging modality immune checkpoint immunogenic immunomodulatory strategy immunoregulation improved in vivo inhibitor lipidomics melanoma monocyte mortality nanodot nanomaterials neoplastic cell neutrophil novel novel strategies novel therapeutics oxidation pharmacologic phospholipid-hydroperoxide glutathione peroxidase prevent quantum repaired standard of care tumor tumor growth tumor microenvironment tumor progression

项目摘要

Project Summary Melanoma is an aggressive and highly metastatic skin cancer. Although modern combination checkpoint inhibitors revolutionized clinical outcomes in advanced cases, over half of all patients are refractory to immunotherapy and require alternative or complementary treatment options. The discovery of ferroptosis provided a novel way to treat cancer. Recently described vulnerability of melanoma cells to ferroptosis offers a new therapeutic opportunity, particularly against the malignant cells which are resistant to current therapies. However, how to exploit such vulnerability is still unclear due to the lack of mechanistic understanding of ferroptosis regulation in melanoma and the tumor-infiltrating immune cells. We discovered that an indiscriminate induction of ferroptosis of the entire tumor tissue has a deleterious impact on protective anti- tumor immune responses, which promotes melanoma progression. Specifically, we found that ferroptotic death of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) in tumors is a major mechanism of immune suppression. Therefore, a shift in the current approach to harness ferroptosis for cancer therapy is required. Only by understanding the regulatory mechanisms of ferroptosis in different cellular compartments of the tumor microenvironment (TME) will we be able to engineer effective melanoma therapy based on the differential modulation of ferroptosis. Utilizing cutting-edge redox lipidomics mass spectrometry and single- cell lipidomics imaging methods, this project will uncover critical mechanisms of ferroptosis regulation in the intratumoral PMN-MDSC and melanoma cells. In addition, we will optimize our recently developed therapeutic approach which will promote ferroptosis of the malignant cells while protecting and enhancing anti-tumor immunity. To achieve these goals, we will pursue three specific aims. In Aim 1, we will decipher how the processes of melanogenesis and cell differentiation regulate melanoma cell susceptibility to ferroptosis. The results will provide a strategic approach to maximizing the efficacy of pro-ferroptotic therapy against melanoma cells. Aim 2 will focus on identifying mechanisms of ferroptosis-mediated immune regulation by PMN-MDSC in melanoma TME. The results will reveal how to protect anti-tumor immune responses via targeted ferroptosis inhibition in the myeloid cells of the TME and prevent immune tolerance to cancer. Finally, in Aim 3 we will expand on our preliminary data to investigate therapeutic potential of differentially regulating ferroptosis in the malignant and the myeloid cells of the melanoma TME. This will be accomplished using our previously developed nano-delivery systems based on graphene quantum nanodots and carbon nanotubes. Such approach is highly clinically relevant as it employs both cytotoxic and immunomodulatory strategies against melanoma aimed at reducing immune tolerance to cancer and overcoming modes of cancer resistance to the standard-of-care combination immune checkpoint and Braf/MEK inhibitors, currently representing a significant clinical challenge.

项目概要黑色素瘤是一种侵袭性且高度转移的皮肤癌。虽然现代组合检查站抑制剂彻底改变了晚期病例的临床结果，超过一半的患者难以治愈免疫疗法并需要替代或补充治疗方案。铁死亡的发现提供了一种治疗癌症的新方法。最近描述的黑色素瘤细胞对铁死亡的脆弱性提供了一个新的治疗机会，特别是针对对当前疗法有抵抗力的恶性细胞。然而，由于缺乏对漏洞的机制理解，如何利用此类漏洞仍不清楚。黑色素瘤和肿瘤浸润免疫细胞中的铁死亡调节。我们发现一个不加区别地诱导整个肿瘤组织的铁死亡对保护性抗-铁死亡具有有害影响肿瘤免疫反应，促进黑色素瘤进展。具体来说，我们发现铁死亡肿瘤中多形核骨髓源性抑制细胞（PMN-MDSC）的死亡是一个主要机制免疫抑制。因此，当前利用铁死亡进行癌症治疗的方法的转变是必须的。只有了解不同细胞区室铁死亡的调控机制肿瘤微环境（TME）的研究将使我们能够设计有效的黑色素瘤治疗铁死亡的差异调节。利用尖端的氧化还原脂质组学质谱和单细胞脂质组学成像方法，该项目将揭示铁死亡调节的关键机制瘤内 PMN-MDSC 和黑色素瘤细胞。此外，我们将优化我们最近开发的治疗方法促进恶性细胞铁死亡同时保护和增强抗肿瘤作用的方法免疫。为了实现这些目标，我们将追求三个具体目标。在目标 1 中，我们将解读如何黑色素生成和细胞分化过程调节黑色素瘤细胞对铁死亡的易感性。这结果将为最大化促铁死亡疗法的功效提供一种战略方法黑色素瘤细胞。目标 2 将侧重于通过以下方式确定铁死亡介导的免疫调节机制：黑色素瘤 TME 中的 PMN-MDSC。结果将揭示如何通过以下方式保护抗肿瘤免疫反应：靶向抑制 TME 骨髓细胞的铁死亡并防止对癌症的免疫耐受。最后，在目标 3 中，我们将扩展我们的初步数据，以研究差异调节的治疗潜力黑色素瘤 TME 的恶性细胞和骨髓细胞中的铁死亡。这将使用我们的先前开发的基于石墨烯量子纳米点和碳纳米管的纳米递送系统。这种方法具有高度的临床相关性，因为它同时采用细胞毒性和免疫调节策略对抗黑色素瘤，旨在降低对癌症的免疫耐受性并克服癌症模式目前对标准护理组合免疫检查点和 Braf/MEK 抑制剂的耐药性代表着重大的临床挑战。