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
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摘要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.
著者Xing R, Li L, Chen L, Gao Z, Wang H, Li W, Cui J, Tian G, Liang Q, Yu J, Sung JJ, Luo G, Gao H, Xu X, Yang H, Wang J, Zhang X, Wang JM, Huang J, Yu Y, Wang J, Lu Y
期刊名稱Oncogene
出版年份2016
月份5
日期19
卷號35
期次20
出版社NATURE PUBLISHING GROUP
頁次2584 - 2591
國際標準期刊號0950-9232
電子國際標準期刊號1476-5594
語言英式英語
Web of Science 學科類別Biochemistry & Molecular Biology; Cell Biology; Genetics & Heredity; Oncology

上次更新時間 2020-25-11 於 02:12