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Copy number variations of HLA-I and activation of NKp30 pathway determine the sensitivity of gastric cancer cells to the cytotoxicity of natural killer cells

Oncogene volume 35, pages 2584–2591 (2016)Cite this article

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Abstract

Nude mice are important in vivo model for characterization of cell malignancy behavior; however, many cancer cells fail to form tumors in it. Understanding this defective mechanism may provide novel insights into tumorigenesis and how tumor cells escape innate immunity. Whole-genome sequencing was conducted on two gastric cancer (GC) cells, BGC823 and AGS, which do and do not form tumors in nude mice, to identify their genomic differences relevant to natural killer (NK) cells. We found that the tumorigenic capacity of human GC cell lines was dependent on the recruitment and activation of NK cells in xenograft tumors. We used whole-genome sequence (WGS) on GC cell lines to identify potential genes controlling susceptibility to NK-mediated killing. The tumorigenic cell line BGC823 expressed high levels of HLA-I because of copy gain and was resistant to NK cell killing. In contrast, another cell line AGS expressing low levels of HLA-I with activated NKp30/MAPK/IL-12 (interleukin-12) or IL-2 (interleukin-2) pathway was susceptible to NK lysis. Treatment of tumor bearing mice with systemic administration of IL-12 in combination with intratumor injection of anti-HLA-I antibody significantly increased NK cell recruitment into xenograft tumors, which became sensitive to NK killing, resulting in reduced tumor progression. In human GC specimens, decreased HLA-I expression and increased NK cells surrounding tumor cells were correlated with decreased metastasis potential and better prognosis of patients. Our results provide a mechanistic basis for GC cells to escape NK lysis and a promising prospect of NK immunotherapy for GC cells.

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Acknowledgements

We thank Dr Richard Ascione (Department of Biochemistry and Molecular Biology, Medical School of Georgetown University USA) and Dr Laurie Goodman for critical reviewing and editing of the manuscript. This work was supported by the Ministry of Science and Technology of China (863 program, grants 2012AA02A203, 2012AA02A504) and Beijing Nova program (XXJH2015037, No.Z151100000315069).

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Author notes

  1. R Xing, L Li, L Chen and Z Gao: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China

    R Xing, H Wang, W Li, J Cui & Y Lu

  2. Beijing Genomics Institute at Shenzhen, Shenzhen, China

    L Li, L Chen, Z Gao, G Tian, X Xu, H Yang, J Wang, X Zhang & J Wang

  3. Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China

    Q Liang, J Yu & J J Sung

  4. Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA

    G Luo

  5. Beijing University of Chinese Medicine, Beijing, China

    G Luo

  6. Shanghai Engineering Center for Molecular Medicine, Shanghai, China

    H Gao

  7. Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, USA

    J M Wang & J Huang

  8. Department of Surgery, Ruijin Hospital and Shanghai Institute of Digestive Surgery, Shanghai Jiao Tong University, School of Medicine, Shanghai, China

    Y Yu

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  1. R Xing
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  16. J Wang
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  19. J Huang
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  20. Y Yu
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  21. J Wang
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  22. Y Lu
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Corresponding authors

Correspondence to J Wang or Y Lu.

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Xing, R., Li, L., Chen, L. et al. Copy number variations of HLA-I and activation of NKp30 pathway determine the sensitivity of gastric cancer cells to the cytotoxicity of natural killer cells. Oncogene 35, 2584–2591 (2016). https://doi.org/10.1038/onc.2015.324

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  • DOI: https://doi.org/10.1038/onc.2015.324

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