Re-engineering differential regulation of ferroptosis in melanoma microenvironment

项目摘要 黑色素瘤是一种侵袭性和高度转移性的皮肤癌。虽然现代的联合检查站 抑制剂革命性地改变了晚期病例的临床结果，超过一半的患者对 免疫疗法，并需要替代或补充治疗选择。铁性上睑下垂的发现 为治疗癌症提供了一种新的方法。最近描述的黑色素瘤细胞对铁下垂的脆弱性 一个新的治疗机会，特别是对抗对当前疗法具有抵抗力的恶性细胞。 然而，由于缺乏机制上的理解，如何利用这种漏洞仍然不清楚 黑色素瘤和肿瘤浸润性免疫细胞中铁下垂的调节。我们发现一个 不加选择地诱导整个肿瘤组织的铁性下垂对保护性抗肿瘤产生有害的影响。 肿瘤免疫反应，促进黑色素瘤进展。具体地说，我们发现铁眼镜蛇 中性粒细胞来源的髓系抑制细胞(PMN-MDSC)在肿瘤中的死亡是一个主要机制 免疫抑制。因此，目前利用铁下垂治疗癌症的方法发生了转变 是必需的。只有了解不同细胞间的铁性下垂的调节机制 在肿瘤微环境(TME)的基础上，我们能否设计有效的黑色素瘤治疗 上睑下垂的差动调制。利用尖端氧化还原类脂组学和单质谱. 细胞脂质组学成像方法，该项目将揭示铁下垂调节的关键机制。 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 在保护和增强抗肿瘤作用的同时促进恶性细胞铁性下垂的方法 豁免权。为了实现这些目标，我们将追求三个具体目标。在目标1中，我们将破译 黑素生成和细胞分化过程调节黑色素瘤细胞对铁性下垂的易感性。这个 研究结果将为最大限度地提高促铁下垂治疗的疗效提供一种战略方法。 黑色素瘤细胞。目标2将集中于确定铁下垂介导的免疫调节机制，通过 黑色素瘤TME中的PMN-MDSC。这一结果将揭示如何通过 靶向抑制TME髓系细胞中的铁下垂，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的恶性细胞和髓样细胞中的铁性下垂。这将使用我们的 以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，因为它同时采用了细胞毒性和免疫调节策略。 抗黑色素瘤，旨在降低对癌症的免疫耐受性和克服癌症的模式 对标准护理联合免疫检查点和BRAF/MEK抑制剂的耐药性，目前 这是一个重大的临床挑战。

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.