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

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.

Enah overexpression is correlated with poor survival and aggressive phenotype in gastric cancer

“…These results correspond to those of previous studies in other cancers 14 , 19 , 29 , 30 .At the same time, in vivo assay using MKN45 and SGC7901 cells also verified the inhibitory and stimulative role of Enah on cell proliferation and metastasis. Here, we did not perform this assay using the AGS cell because in 2016, R Xing 31 and colleagues confirmed that the GC cell line AGS, which expresses low level of HLA-I upon activation of the NKp30/MAPK/interleukin (IL)-12 or IL-2 pathway, was susceptible to NK cell-mediated lysis, leading to the failure of AGS cells to form tumors in nude mice. Altogether, our data demonstrate that Enah plays an important role in GC pathogenesis by the promotion of cell proliferation and metastesis and the inhibition of apoptosis.…”

Exploration of signature based on T cell-related genes in stomach adenocarcinoma by analysis of single cell sequencing data

“…Several common immune checkpoints (CD274, CTLA-4, LAG3, PD-CD1, ATIC) were identified to be highly expressed in low-risk populations for better clinical application of ICI. HLA acts as an antigen presenting factor regulating immune response in gastric cancer [ 40 ]. Lower risk group had higher expression of HLA-related genes, indicating a more active local immune response.…”

Tumor microenvironment-mediated immune tolerance in development and treatment of gastric cancer

“…Although NK cells in the resting state have little cytotoxicity against GC, NK cells induced by the K562-mb15-41BBL cell line in vitro have strong effects on GC cytotoxicity and strong antitumor activity in animal experiments ( 45 ). Decreased human leukocyte antigen class I (HLA-I) expression leads to decreased NK cell infiltration in GC and is insensitive to NK cell activity ( 46 ). Death-associated protein kinase 1 (DAPK1) downregulates the IKKβ/CSN5 axis in GC, inhibits PD-L1 expression, and activates the killing ability of NK cells ( 47 ).…”