Abstract
Relapse and metastasis of nasopharyngeal carcinoma (NPC) are presumably attributed to cancer stem cells (CSCs). In recent years, chimeric antigen receptor (CAR)-modified immune effector cells have been shown to have impressive antitumour efficacy. In this study, we aimed to identify appropriate tumour-associated antigens predominantly expressed on NPC stem cells (NPCSCs) and determine their suitability for CAR-engineered cytokine-induced killer (CIK) cell therapy against NPC. By investigating the expression patterns of potential target antigens (ROR1, 5T4 and CAIX) in NPC, we found that the oncofetal antigen 5T4 was predominately expressed in NPC cell lines and tissues but absent in non-cancerous nasopharyngeal tissues. Moreover, significantly enhanced expression of 5T4 in NPC spheroids revealed its relationship with putative NPCSCs. Hence, we designed a CAR construct (5T4-28Z) specific for 5T4 and generated CAR-transduced CIK cells. Our results showed that the artificial CAR was efficiently expressed on the surface of CIK cells and that no native phenotypes were altered by the gene transduction. Functional assays revealed that 5T4-28Z-CIK cells possessed both CAR-mediated and CAR-independent anti-NPC activity and were capable of efficiently attacking NPC cells, especially NPCSC-like cells in vitro, suggesting that they might serve as an attractive tool for developing efficient therapies against NPC.
Highlights
Nasopharyngeal carcinoma (NPC), a distinctive head and neck malignancy originating from nasopharyngeal epithelium, is highly prevalent in South China and Southeast Asia, with an annual incidence of more than 25 cases per 100,000 individuals[1]
cytokine-induced killer (CIK) cells exhibit major histocompatibility complex (MHC) unrestricted, antigen-independent cytolytic activity against various tumour cells, including cancer stem cells (CSCs)-like cells. This effect is primarily mediated by an interaction between the activating natural killer cell receptors of CIK cells including natural killer group 2 member D (NKG2D) and the corresponding ligands expressed on the surface of tumour cells[10]
real-time quantitative PCR (RT-qPCR) detection revealed that the 5T4 transcription levels in the same five nasopharyngeal carcinoma (NPC) cell lines were over four times higher than that of the NP69 cell line (Fig. 1b)
Summary
Nasopharyngeal carcinoma (NPC), a distinctive head and neck malignancy originating from nasopharyngeal epithelium, is highly prevalent in South China and Southeast Asia, with an annual incidence of more than 25 cases per 100,000 individuals[1]. CIK cells exhibit major histocompatibility complex (MHC) unrestricted, antigen-independent cytolytic activity against various tumour cells, including CSC-like cells This effect is primarily mediated by an interaction between the activating natural killer cell receptors of CIK cells including natural killer group 2 member D (NKG2D) and the corresponding ligands expressed on the surface of tumour cells[10]. The clinical therapeutic efficacy is limited primarily due to the moderate activation of CIK cells, which has restricted their extensive application This insufficient activation is mainly attributed to the nonspecific recognition pattern of CIK cells and immune tolerance resulting from multiple mechanisms that tumours employ to evade immune surveillance[12]. This result suggests that novel therapeutic strategies with superior specificity and efficacy for treating malignancies are imperative. These effects are mainly attributed to the recognition of target antigens at low expression levels on normal tissues by CARs, prompting researchers to be more rigorous and prudent in the selection of target antigens for CAR-redirected immunotherapy
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