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

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Abstract

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.

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Acknowledgements

This research was supported by a grant (NMRC/BnB/018b/2015) from the National Medical Research Council (NMRC), Singapore to H.S. and by A*STAR core funding and Singapore NRF under its NRF-SIS “SingMass” scheme to R.M.S. J.K.T. is supported by the Transition Award (TA20nov-0025) from NMRC, and K.S.L is supported by the Individual Research Grant (CIRG18nov-0045) from NMRC. We thank the LSI core facility under the leadership of Dr. Paul Hutchinson for excellent help with flow cytometry.

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  1. Mukul Prasad and Sashigala Ponnalagu have contributed equally to this work.

Authors and Affiliations

  1. Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 2 Medical Dr., Singapore, 117593, Singapore

    Mukul Prasad, Sashigala Ponnalagu, Qun Zeng, Khang Luu, Si Min Lang, Hiu Yi Wong, Man Si Cheng, Meihui Wu, Karthik Mallilankaraman & Herbert Schwarz

  2. NUS Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore, Singapore

    Mukul Prasad, Sashigala Ponnalagu, Qun Zeng, Khang Luu, Si Min Lang, Hiu Yi Wong, Man Si Cheng, Meihui Wu & Herbert Schwarz

  3. NUSMED Immunology Translational Research Programme, National University of Singapore, Singapore, Singapore

    Mukul Prasad, Sashigala Ponnalagu, Qun Zeng, Khang Luu, Si Min Lang, Hiu Yi Wong, Man Si Cheng, Meihui Wu & Herbert Schwarz

  4. Center for Healthy Longevity, National University Health System, Singapore, Singapore

    Karthik Mallilankaraman

  5. Functional Proteomics Laboratory, SingMass National Laboratory, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore

    Radoslaw Mikolaj Sobota, Yan Ting Lim & Loo Chien Wang

  6. Department of Haematology-Oncology, National University Cancer Institute, Singapore, National University Health System, Singapore, Singapore

    Chuan Keng Goh, Kai Xun Joshua Tay & Boon Cher Goh

  7. Department of Otolaryngology – Head and Neck Surgery, National University of Singapore, Singapore, Singapore

    Kwok Seng Loh

  8. Singapore Immunology Network, Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore

    Cheng-I. Wang & Wen-Hsien Lee

  9. Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore

    Boon Cher Goh

  10. Department of Otolaryngology – Head and Neck Surgery, Singapore General Hospital, Singapore, Singapore

    Chwee Ming Lim

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  1. Mukul Prasad
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Prasad, M., Ponnalagu, S., Zeng, Q. et al. Epstein-Barr virus-induced ectopic CD137 expression helps nasopharyngeal carcinoma to escape immune surveillance and enables targeting by chimeric antigen receptors. Cancer Immunol Immunother 71, 2583–2596 (2022). https://doi.org/10.1007/s00262-022-03183-8

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