Epstein-Barr virus-induced ectopic CD137 expression helps nasopharyngeal carcinoma to escape immune surveillance and enables targeting by chimeric antigen receptors.

Non-keratinizing nasopharyngeal carcinoma (NPC) is a malignancy with a poor prognosis for relapsing patients and those with metastatic disease. Here, we identify a novel disease mechanism of NPC which may be its Achilles' heel that makes it susceptible to immunotherapy. CD137 is a potent costimulatory receptor on activated T cells, and CD137 agonists strongly enhance anti-tumor immune responses. A negative feedback mechanism prevents overstimulation by transferring CD137 from T cells to CD137 ligand (CD137L)-expressing antigen presenting cells (APC) during cognate interaction, upon which the CD137-CD137L complex is internalized and degraded. We found ectopic expression of CD137 on 42 of 122 (34.4%) NPC cases, and that CD137 is induced by the Epstein-Barr virus latent membrane protein (LMP) 1. CD137 expression enables NPC to hijack the inbuilt negative feedback mechanism to downregulate the costimulatory CD137L on APC, facilitating its escape from immune surveillance. Further, the ectopically expressed CD137 signals into NPC cells via the p38-MAPK pathway, and induces the expression of IL-6, IL-8 and Laminin γ2. As much as ectopic CD137 expression may support the growth and spread of NPC, it may be a target for its immunotherapeutic elimination. Natural killer cells that express a CD137-specific chimeric antigen receptor induce death in CD137+ NPC cells, in vitro, and in vivo in a murine xenograft model. These data identify a novel immune escape mechanism of NPC, and lay the foundation for an urgently needed immunotherapeutic approach for NPC.

COVID-19 post-vaccination lymphadenopathy: Report of cytological findings from fine needle aspiration biopsy.

The coronavirus COVID-19 pandemic has spurred the rapid development of vaccines, with vaccination programmes already underway in many countries. Regional lymphadenopathy is one of the documented side effects of vaccination. We document the fine needle aspiration cytological findings of an enlarged supraclavicular lymph node in a 34-year-old Asian female following the first dose of the Pfizer-BioNTech COVID-19 mRNA vaccine, which appears to be the first such report in a premorbidly well patient with no known history of malignancy. The cytological findings featured a reactive pattern in keeping with follicular hyperplasia, with prominent germinal centre elements including lymphohistiocytic aggregates and tingible-body macrophages. Despite an increased proportion of larger lymphocytes, the overall pattern was in keeping with a reactive pattern, bearing in mind the temporal and geographic relation to the vaccination injection. In instances of localised lymphadenopathy, particularly in supraclavicular or axillary locations, pathologists should be cognizant of the possibility of post-vaccination reactive lymphadenopathy, and seek clinical and radiological hints favouring a benign process, whilst recognising potential morphological overlaps with lymphoproliferative disorders. Awareness of this diagnostic pitfall is especially important as COVID-19 vaccination coverage is ramped up worldwide, leading to an expected increase in incidence of post-vaccination reactive lymphadenopathy.