Cancer Immunotherapy via Targeting Cancer Stem Cells Using Vaccine Nanodiscs

Abstract

Cancer stem cells (CSCs) proliferate extensively and drive tumor metastasis and recurrence. CSCs have been identified in over 20 cancer types to date, but it remains unknown how to target and eliminate CSCs in vivo. Aldehyde dehydrogenase (ALDH) is a marker that has been used extensively for isolating CSCs. Here we present a novel approach to target and reduce the frequency of ALDH high CSCs by vaccination against ALDH. We have identified ALDH1-A1 and ALDH1-A3 epitopes from CSCs and developed synthetic high-density lipoprotein nanodiscs for vaccination against ALDH high CSCs. Nanodiscs increased antigen trafficking to lymph nodes and generated robust ALDH-specific T cell responses. Nanodisc vaccination against ALDH high CSCs combined with anti-PD-L1 therapy exerted potent antitumor efficacy and prolonged animal survival in multiple murine models. Overall, this is the first demonstration of a simple nanovaccine strategy against CSCs and may lead to new avenues for cancer immunotherapy against CSCs.

The Multifaceted Role of Aldehyde Dehydrogenases in Prostate Cancer Stem Cells

“…In addition, it has been shown that crosstalk between immune cells and ALDH+ tumor cells is reciprocal, as the targeting of tumor-associated myeloid cells by the inhibition of colony-stimulating factor 1 receptor (CSF1R) resulted in the depletion of the ALDH+ CSC population in pancreatic ductal adenocarcinoma (PDAC) tumors [214][215][216]. The development of the anti-ALDH vaccines and their clinical testing in combination with immune checkpoint inhibitors can be an efficient strategy to eradicate CSC populations and improve the tumor therapy response [206][207][208].…”

“…Recent studies on the dendritic cell (DC)-based vaccines demonstrated that the DC pulsed by the cell lysates of ALDH + CSCs inhibited primary and metastatic tumor growth in the vaccinated xenograft tumor models. As for now, the CSC–DC vaccines were successfully tested for several tumor entities, including melanoma, head and neck squamous cell carcinoma (HNSCC), and breast cancer [ 206 , 207 , 208 ]. Thus, targeting CSCs with these vaccines alone or in combination with immune checkpoint inhibitors may lead to new avenues for anticancer immunotherapy.…”

The Tumor Microenvironment as a Driving Force of Breast Cancer Stem Cell Plasticity

“…Although ongoing clinical trials are still evaluating its potential benefits in BC [ 218 ], this example serves as an illustration of the possibilities of such strategies. Additionally, immunotherapy is emerging as a promising tool to manipulate the TME and target BCSCs, directly or indirectly [ 115 , 219 , 220 , 221 , 222 , 223 ].…”

Targeting Neuroinflammation in Brain Cancer: Uncovering Mechanisms, Pharmacological Targets, and Neuropharmaceutical Developments

“…Aside from TAAs and neoantigens, cancer stem cells (CSCs) and other non-neoplastic compartments may serve as potential targets for gliomas. Nanodiscs delivering CSC-derived ALDH1-A1 and -A3 peptides have been shown to induce potent anti-tumor activity and prolong animal survival in multiple mouse models ( Hassani Najafabadi et al, 2020 ). Overall, sHDL nanodisc serves as a versatile platform with potent anti-tumor efficacy.…”