Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA.
Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA; Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA; Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
J Control Release. 2022 Nov;351:872-882. doi: 10.1016/j.jconrel.2022.09.061. Epub 2022 Oct 10.
One of the major reasons for poor cancer outcomes is the existence of cancer stem cells (CSCs). CSCs are a small subpopulation of tumor cells that can self-renew, differentiate into the majority of tumor cells, and maintain tumorigenicity. As CSCs are resistant to traditional chemotherapy and radiation, they contribute to metastasis and relapse. Thus, new approaches are needed to target and eliminate CSCs. Here, we sought to target and reduce the frequency of CSCs in melanoma by therapeutic vaccination against CSC-associated transcription factors, such as Sox2 and Nanog, and aldehyde dehydrogenase (ALDH). Toward this goal, we have identified novel immunogenic peptide epitopes derived from CSC-associated Sox2 and Nanog and synthesized synthetic high-density lipoprotein (sHDL) nanodisc vaccine formulated with Sox2, Nanog, and ALDH antigen peptides together with CpG, a Toll-like receptor 9 agonist. Vaccination with nanodiscs containing six CSC antigen peptides elicited robust T cell responses against CSC-associated antigens and promoted intratumoral infiltration of CD8+ T cells, while reducing the frequency of CSCs and CD4+ regulatory T cells within melanoma tumors. Nanodisc vaccination effectively reduced tumor growth and significantly extended animal survival without toxicity toward normal stem cells. Overall, our therapeutic strategy against CSCs represents a cost-effective, safe, and versatile approach that may be applied to melanoma and other cancer types, as well as serve as a critical component in combined therapies to target and eliminate CSCs.
癌症治疗效果不佳的一个主要原因是癌症干细胞 (CSC) 的存在。CSC 是肿瘤细胞中的一小部分亚群，能够自我更新、分化为大多数肿瘤细胞，并维持肿瘤的发生。由于 CSC 对传统的化疗和放疗具有抗性，它们导致了转移和复发。因此，需要新的方法来靶向和消除 CSC。在这里，我们试图通过针对 CSC 相关转录因子（如 Sox2 和 Nanog）和醛脱氢酶 (ALDH) 的治疗性疫苗来靶向和减少黑色素瘤中的 CSC 频率。为了实现这一目标，我们已经鉴定了源自 CSC 相关 Sox2 和 Nanog 的新型免疫原性肽表位，并合成了含有 Sox2、Nanog 和 ALDH 抗原肽的高密度脂蛋白 (HDL) 纳米盘疫苗，并与 TLR9 激动剂 CpG 一起进行了配制。用含有六个 CSC 抗原肽的纳米盘进行疫苗接种会引发针对 CSC 相关抗原的强烈 T 细胞反应，并促进 CD8+T 细胞在肿瘤内浸润，同时减少黑色素瘤肿瘤中 CSC 和 CD4+调节性 T 细胞的频率。纳米盘疫苗接种有效地抑制了肿瘤生长并显著延长了动物的存活时间，而对正常干细胞没有毒性。总的来说，我们针对 CSC 的治疗策略代表了一种具有成本效益、安全性和多功能性的方法，可应用于黑色素瘤和其他癌症类型，并可作为联合治疗的关键组成部分，用于靶向和消除 CSC。
