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

Wei Peng; Liang Chang; Wenqiang Li; Yanan Liu; Min Zhang

doi:10.3389/fonc.2022.781093

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

Front Oncol. 2022 Mar 24:12:781093. doi: 10.3389/fonc.2022.781093. eCollection 2022.

Authors

Wei Peng¹, Liang Chang¹, Wenqiang Li¹, Yanan Liu², Min Zhang³

Affiliations

¹ Department of General Surgery, Guangdong Provincial People's Hospital Zhuhai Hospital (Zhuhai Golden Bay Center Hospital), Zhuhai, China.
² Department of Intensive Care Unit, Guangdong Provincial People's Hospital Zhuhai Hospital (Zhuhai Golden Bay Center Hospital), Zhuhai, China.
³ Department of General Surgery, Cixi People's Hospital, Ningbo, China.

Abstract

Purpose: This 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.

Methods: In 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.

Results: OCT4 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.

Conclusion: OCT4&SOX2 CTLs exhibit good efficiency and synergize PD-1 inhibitor (nivolumab) in treating BCSCs and DRBC.

Keywords: OCT4 and SOX2; PD-1 inhibitor; breast cancer stem-like cells; cytotoxic T lymphocytes; drug-resistance breast cancer.