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

• Published in: Cancer Immunology, Immunotherapy Vol. 71; no. 11; pp. 2583 - 2596
• Main Authors: Prasad, Mukul, Ponnalagu, Sashigala, Zeng, Qun, Luu, Khang, Lang, Si Min, Wong, Hiu Yi, Cheng, Man Si, Wu, Meihui, Mallilankaraman, Karthik, Sobota, Radoslaw Mikolaj, Lim, Yan Ting, Wang, Loo Chien, Goh, Chuan Keng, Tay, Kai Xun Joshua, Loh, Kwok Seng, Wang, Cheng-I., Lee, Wen-Hsien, Goh, Boon Cher, Lim, Chwee Ming, Schwarz, Herbert
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.11.2022; Springer Nature B.V
• Subjects: 4-1BB Ligand; Adenomatous polyposis coli; Animals; Antigen-presenting cells; Antigens; Cancer Research; CD137 antigen; Cell death; Chimeric antigen receptors; Ectopic expression; Epstein-Barr virus; Epstein-Barr Virus Infections; Feedback; Herpesvirus 4, Human; Humans; Immunology; Immunosurveillance; Immunotherapy; Interleukin 6; Interleukin 8; Laminin; Lymphocytes T; Malignancy; MAP kinase; Medicine; Medicine & Public Health; Membrane proteins; Metastases; Mice; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Natural killer cells; Neoplasm Recurrence, Local; Oncology; Original; Original Article; Receptors, Chimeric Antigen; Throat cancer; Tumor Necrosis Factor Receptor Superfamily, Member 9; Tumors; Xenografts; Nasopharyngeal carcinoma; Immune evasion; CD137; Trogocytosis; IL-8; IL-6
• ISSN: 0340-7004; 1432-0851; 1432-0851
• DOI: 10.1007/s00262-022-03183-8

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.