Abstract 5514: Therapeutic potential of activated natural killer cells in nasopharyngeal carcinoma

Abstract

Abstract One of the key features of nasopharyngeal carcinoma (NPC) is dense lymphocyte infiltration. Despite elevated lymphocyte populations in tumor microenvironment, these lymphocytes have modest killing activity. One of the possible speculations is constitutive STAT3 overexpression within NPC microenvironment which results in immunosuppression of cytolytic immune cells. Natural killer (NK) cells act as first line defense of innate immunity through cytolytic killing of virus-infected cells and/or cancer cells. Unlike T cells, NK killing does not require antigen presentation and therefore would be effective even for MHC defective cancers. This makes NK therapy attractive in form of autologous and allogeneic transfer. Here we hypothesized that activated NK cells would show enhanced anti-NPC activity. We also sought to investigate the potential of combined NK with STAT3 inhibitor in NPC treatment. In this study, NK cells from peripheral blood mononuclear cells (PBMC) of healthy donors (N=3) were isolated and expanded. Three Epstein Barr Virus (EBV) positive NPC cell lines (NPC43, C666-1, C17) were employed in this study. Naïve and activated NK cells were subjected to NPC coculture at various effector: target (E:T) cell ratios. In combination treatment with NK cells, a small molecule inhibitor Napabucasin was employed for STAT3 treatment. NK killing activity was assessed through flow cytometry analysis of NPC cell death. The current study demonstrated significant elevation of NK activation marker expressions after 4 weeks of ex vivo expansion (CD69 34.7±2.3 fold, p=0.002; NKG2D 4.2±0.8 fold, p=0.018). Concomitantly, ex vivo activated NK cells demonstrated augmented killing activity against NPC cells at a dose-dependent manner, compared to their naïve status (p<0.001). In NPC43, net cytotoxicity of expanded NK was 35.5±7.2% compared to naïve NK with only 2.5±4.3% (p=0.003). NPC43 was most sensitive towards NK killing, followed by C666-1, then C17. This corresponds to NPC43’s low PD-L1 protein expression, a known downstream STAT3 target and immune checkpoint molecule. In addition, activated NK could kill chemoresistant NPC cells indiscriminately compared to the paralleled parental cells (18.5±2.3% and 16.1±3.8%, p=0.589). Importantly, augmented NPC43 cell death was observed in combined treatment (47.1±2.1%) compared to single treatment (NK alone: 9.2±6.5%; Napabucasin alone: 25.0±4.5%). In summary, this work demonstrated encouraging therapeutic potential of both NK therapy and in combination with STAT3 inhibitor Napabucasin for NPC treatment. Citation Format: Shinyee Hui, Kwok Wai Lo, Mingjing Xu, Siu Tim Cheung. Therapeutic potential of activated natural killer cells in nasopharyngeal carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5514.