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The lack of representative nasopharyngeal carcinoma (NPC) models has seriously hampered research on EBV carcinogenesis and preclinical studies in NPC. Here we report the successful growth of five NPC patient-derived xenografts (PDXs) from fifty-eight attempts of transplantation of NPC specimens into NOD/SCID mice. The take rates for primary and recurrent NPC are 4.9% and 17.6%, respectively. Successful establishment of a new EBV-positive NPC cell line, NPC43, is achieved directly from patient NPC tissues by including Rho-associated coiled-coil containing kinases inhibitor (Y-27632) in culture medium. Spontaneous lytic reactivation of EBV can be observed in NPC43 upon withdrawal of Y-27632. Whole-exome sequencing (WES) reveals a close similarity in mutational profiles of these NPC PDXs with their corresponding patient NPC. Whole-genome sequencing (WGS) further delineates the genomic landscape and sequences of EBV genomes in these newly established NPC models, which supports their potential use in future studies of NPC.

Simple Summary: Nasopharyngeal carcinoma (NPC) is a malignancy prevalent in Southeast Asia with the highest metastatic rate amongst other head and neck cancers. The absence of symptoms and unique anatomical positioning often result in late diagnosis, with resistance to chemo/radiotherapy further impacting its prognosis. While immunotherapies such as immune-checkpoint inhibitors (ICIs) and cytotoxic-T-lymphocytes (CTLs)-based cellular therapy have been progressively developed and approved, the mechanisms underlying the immunosuppressive tumour microenvironment (TME) in NPC remain poorly understood. Exosomes, small extracellular vesicles ranging in size from 30 to 150 nm, have emerged as important mediators of cell–cell communications within the TME. Accumulating evidence points tumour-derived exosomes (TEX) to NPC immune evasion and progression. Additionally, the detectability of TEX-bound NPC-specific markers in bodily fluids shows promise in enabling early diagnosis and prognostication. In this review, we aim to uncover TEX-mediated cellular–pathogenic pathways to open new avenues for an immunotherapeutic regimen in NPC and highlight the potential of exosome-based biomarkers in bettering NPC outcomes. Nasopharyngeal carcinoma (NPC) is an epithelial malignancy situated in the posterolateral nasopharynx. NPC poses grave concerns in Southeast Asia due to its late diagnosis. Together with resistance to standard treatment combining chemo- and radiotherapy, NPC presents high metastatic rates and common recurrence. Despite advancements in immune-checkpoint inhibitors (ICIs) and cytotoxic-T-lymphocytes (CTLs)-based cellular therapy, the exhaustive T cell profile and other signs of immunosuppression within the NPC tumour microenvironment (TME) remain as concerns to immunotherapy response. Exosomes, extracellular vesicles of 30–150 nm in diameter, are increasingly studied and linked to tumourigenesis in oncology. These bilipid-membrane-bound vesicles are packaged with a variety of signalling molecules, mediating cell–cell communications. Within the TME, exosomes can originate from tumour, immune, or stromal cells. Although there are studies on tumour-derived exosomes (TEX) in NPC and their effects on tumour processes like angiogenesis, metastasis, therapeutic resistance, there is a lack of research on their involvement in immune evasion. In this review, we aim to enhance the comprehension of how NPC TEX contribute to cellular immunosuppression. Furthermore, considering the detectability of TEX in bodily fluids, we will also discuss the potential development of TEX-related biomarkers for liquid biopsy in NPC as this could facilitate early diagnosis and prognostication of the disease. [ABSTRACT FROM AUTHOR]

[Display omitted] • High ENOX2 expression is associated with immune excluded/deserted phenotypes in NPC. • ENOX2 inhibitor, idronoxil enhances CD8+ memory T -cell immunity in response to chemotherapy. • Combined treatment with idronoxil and cisplatin enhances tumor response in humanized mice model. • Combined treatment increases CD8+ T -cell expansion with cytolytic effector memory (Tem) feature. • T -cell infiltrates and tumor-associated ENOX2 have predictive value for anti-tumor response. The immunosuppressive tumor microenvironment is a major barrier for chemotherapy. Different chemosensitization approaches to reinstate immunological surveillance for cancers that are immune quiescent at the outset, have thus been devised. Cancer-specific ENOX2 expression is correlated with abnormal cell growth and has been proposed as a cellular target for anti-cancer activity. However, the potential effects of ENOX2 on the interaction between immune system and tumor cells remain elusive. To understand the mechanisms by which tumor-intrinsic ENOX2-mediated alterations in anti-tumor activity of T -cells and response to chemotherapy. In situ multiplexed immunohistochemistry with single cell and bulk RNA sequencing data from nasopharyngeal carcinoma (NPC) human tissues were used to define tumor phenotypes. Two NPC cell lines, with distinct ENOX2 expression, were used in a co-culture platform to study tumor-immune interactions between cancer cells/spheroids and T -cells. The effect of cisplatin treatment with ENOX2 inhibition by idronoxil (IDX) were tested in vitro and in vivo. Multi-parametric flow cytometry was used to characterize T -cell infiltrates in an NPC tumor humanized mouse model treated with combined treatment. NPC predominantly displayed an immune-excluded profile. This "cold-phenotype" was shown to exhibit higher ENOX2 expression and was associate with poorer progression-free survival (PFS). The therapeutic combination of IDX with cisplatin was effective in promoting CD8+ effector memory T cell (Tem) differentiation and mobilization. This Tem signature was highly cytotoxic, with Tem-mediated preferential lysis of higher ENOX2-expressing NPC cells. A combination-treated humanized mouse model showing dramatic shrinkage in tumors, were intra-tumoral Tem-enriched. Tumor-intrinsic ENOX2 expression is associated with tumor phenotype and PFS in NPC. Targeting ENOX2 with IDX and cisplatin impose qualitative control of T -cell response by preferentially increasing immune cells infiltration, Tem differentiation and tumor suppression. We suggest that ENOX2 inhibition may be a promising therapeutic strategy to enhance the effects of chemotherapy. [ABSTRACT FROM AUTHOR]

Most mature B cells can be divided into four subtypes based on the expression of the surface markers IgD and CD27: IgD+CD27− naïve B cells, IgD+CD27+ unswitched memory B cells, IgD−CD27+ switched memory B cells, and IgD−CD27− double‐negative (DN) B cells. Despite their small population size in normal peripheral blood, DN B cells play integral roles in various diseases. For example, they generate autoimmunity in autoimmune conditions, while these cells may generate both autoimmune and antipathogenic responses in COVID‐19, or act in a purely antipathogenic capacity in malaria. Recently, DN B cells have been identified in nasopharyngeal carcinoma and non‐small‐cell lung cancers, where they may play an immunosuppressive role. The distinct functions that DN B cells play in different diseases suggest that they are a heterogeneous B‐cell population. Therefore, further study of the mechanisms underlying the involvement of DN B cells in these diseases is essential for understanding their pathogenesis and the development of therapeutic strategies. Further research is thus warranted to characterize the DN B‐cell population in detail. [ABSTRACT FROM AUTHOR]