A research team at LKS Faculty of Medicine, The University of Hong Kong (HKUMed) discovered that exosomes derived from γδ-T cells (γδ-T-Exos) synergised with radiotherapy can control nasopharyngeal carcinoma (NPC) by overcoming the radioresistance of NPC cancer stem cells (CSCs) and preserve their tumour-killing and T cell-promoting activities in the immunosuppressive NPC microenvironment. This study provides a proof of concept for a novel and potent strategy by combining γδ-T-Exos with radiotherapy in the control of NPC. The ground-breaking findings have been published in the leading academic journal, Journal for Immunotherapy of Cancer.

Nasopharyngeal carcinoma (NPC) is one of the most aggressive Epstein-Barr virus (EBV)-associated tumours, which are very prevalent in East Asia, including Hong Kong. Radiotherapy is the first-line treatment for NPC, but its therapeutic efficacy is poor in some patients due to radioresistance. Adoptive T cell-based immunotherapy has also shown promise to control NPC; however, its anti-tumour efficacy may be attenuated by an immunosuppressive tumour microenvironment. Exosomes are endosome-originated small extracellular vesicles that mediate intercellular communication. Compared with cell-based therapy, cell-free exosomes have advantages with higher safety, easier storage and lower costs. In a previous study, researchers have demonstrated that γδ-T-Exos could effectively control the progression of EBV-associated tumours. However, it remains unknown whether γδ-T-Exos have synergistic effect with radiotherapy and preserve their anti-tumour activities against NPC in an immunosuppressive tumour microenvironment.

Herein, the research team found that γδ-T-Exos not only effectively interacted with NPC cells and induced tumour cell death in vitro, which was mainly mediated by Fas/Fas ligand (FasL) and death receptor 5 (DR5)/tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) pathways, but also controlled NPC tumour growth and prolonged tumour-bearing mice survival in vivo. Furthermore, γδ-T-Exos selectively targeted the radioresistant CD44+/high CSCs and induced profound cell apoptosis. The combination of γδ-T-Exos with radiotherapy overcame the radioresistance of CD44+/high NPC cells and significantly improved its therapeutic efficacy against NPC in vitro and in vivo. In addition, γδ-T-Exos promoted T-cell migration into NPC tumours by upregulating CCR5 on T cells that were chemoattracted by CCR5 ligands in the NPC tumour microenvironment. Although NPC tumour cells secreted abundant tumour growth factor beta (TGF-β) to suppress T- cell responses, γδ-T-Exos preserved their direct anti-tumour activities and overcame the immunosuppressive NPC microenvironment to amplify T-cell anti-tumour immunity.