OCT4 and SOX2 Specific Cytotoxic T Cells Exhibit Not Only Good Efficiency but Also Synergize PD-1 Inhibitor (Nivolumab) in Treating Breast Cancer Stem-Like Cells and Drug-Resistant Breast Cancer Mice

Abstract

PurposeThis study aimed to investigate the effect of OCT4&SOX2 specific cytotoxic T lymphocytes (CTLs) plus programmed cell death protein-1 (PD-1) inhibitor (nivolumab) on treating breast cancer stem-like cells (BCSCs) in vitro and drug-resistance breast cancer (DRBC) mice in vivo.MethodsIn total, 160 breast cancer patients were enrolled following the immunofluorescence assay to detect tumor OCT4 and SOX2 expressions. CD154-activated B cells were co-cultured with CD8+ T cells (from breast cancer patients) in the presence of OCT4&SOX2 peptides, CMV pp65 peptides (negative control), and no peptides (normal control). MCF7-BCSCs were constructed by drug-resistance experiment and sphere-formation assay, then DRBC mice were constructed by planting MCF7-BCSCs. Subsequently, different doses of OCT4&SOX2 CTLs and PD-1 inhibitor (nivolumab) were used to treat MCF7-BCSCs and DRBC mice.ResultsOCT4 and SOX2 correlated with poor differentiation, more advanced stage, and worse prognosis in breast cancer patients. In vitro, OCT4&SOX2 CTLs with effector-target ratio (ETR) 5:1, 10:1 and 20:1 presented with increased cytotoxic activity compared to CMV pp65 CTLs with ETR 20:1 (negative control) and Control CTLs with ETR 20:1 (normal control) on killing MCF7-BCSCs. Besides, PD-1 inhibitor (nivolumab) improved the cytotoxic activity of OCT4&SOX2 CTLs against MCF7-BCSCs in a dose-dependent manner. In vivo, OCT4&SOX2 CTLs plus PD-1 inhibitor (nivolumab) decreased tumor volume and tumor weight while increased tumor apoptosis rate compared to OCT4&SOX2 CTLs alone, PD-1 inhibitor (nivolumab) alone, and control.ConclusionOCT4&SOX2 CTLs exhibit good efficiency and synergize PD-1 inhibitor (nivolumab) in treating BCSCs and DRBC.

Dauricine attenuates Oct4/sonic hedgehog co‐activated stemness and induces reactive oxygen species‐mediated mitochondrial apoptosis via AKT/β‐catenin signaling in human neuroblastoma and glioblastoma stem‐like cells

“…is identified as a terminal effector in the carcinogenic Hh, PI3K/AKT, and Wnt/β-catenin signaling pathway, so it is expected to be a novel target for cancer treatment to prolong the survival of patients by maintaining stemness properties of CSCs (Peng et al, 2022). However, little is known about the functions and mechanism of Oct4 in neuroblastoma and glioblastoma stem cells, and studies on the drugs targeting Oct4 are scarce.…”

“…CSCs is a type of cells with exceptional proliferative and self‐renewal ability in the tumor, which is found to be the origin of tumor and is critical for the maintenance of tumor growth (Liu et al, 2020). Oct4 is identified as a terminal effector in the carcinogenic Hh, PI3K/AKT, and Wnt/β‐catenin signaling pathway, so it is expected to be a novel target for cancer treatment to prolong the survival of patients by maintaining stemness properties of CSCs (Peng et al, 2022). However, little is known about the functions and mechanism of Oct4 in neuroblastoma and glioblastoma stem cells, and studies on the drugs targeting Oct4 are scarce.…”