Human Leukocyte Antigen-G Inhibits the Anti-Tumor Effect of Natural Killer Cells via Immunoglobulin-Like Transcript 2 in Gastric Cancer

Abstract

Background/Aims: Human leukocyte antigen-G (HLA-G) plays an important role in inhibiting natural killer (NK) cell function and promoting immune escape. However, the specific mechanism of HLA-G on NK in gastric cancer (GC) remains not well understood. This study investigated the expression of HLA-G in GC and the role of HLA-G-effected NK cells in GC progression. Methods: HLA-G expression in GC tissues obtained from 49 patients with GC was analyzed by immunohistochemistry and western blot. The number of tumor-infiltrating NK cells and the expression of their surface receptors were analyzed by immunohistochemistry and flow cytometry, respectively. The effect of HLA-G on NK cell proliferation was examined by Cell Counting Kit-8 (CCK8) assay. LDH release assay was used to evaluate the effect of HLA-G on the cytotoxic activity of NK cells, and the levels of IFN-γ and TNF-α in the co-cultured supernatant were detected by ELISA. Mice bearing a xenograft tumor model were used to examine the effect of HLA-G on the anti-tumor effect of NK cells. Results: HLA-G positive expression was detected in most of the GC tissues, and was correlated with the adverse prognosis of the disease. The expression of HLA-G was negatively associated with the number of tumor-infiltrating NK cells. Furthermore, GC cell lines with overexpressed HLA-G revealed their ability to inhibit the cell proliferation and cytotoxic activity of NK-92MI cells, and reduce the secretion of IFN-γ and TNF-α through immunoglobulin-like transcript 2 (ILT2). Finally, this in vivo experiment was able to prove that HLA-G can inhibit the anti-tumor effect of NK cells through ILT2. Conclusion: The expression of HLA-G was strongly correlated with the adverse prognosis of GC. The reason may be that it inhibits the proliferation and cytotoxic activity of infiltrating NK cells through ILT2.

NK Cell-Based Immune Checkpoint Inhibition

“…HLA-G1/ILT2 interaction was also shown to mitigate MICA/NKG2D activation by inhibiting NK cytotoxicity (117). In gastric cancers, HLA-G/ILT2 interaction led to inhibition of infiltrating NK cell proliferation and cytotoxicity (118). HLA-G plasma expression in B-cell malignancies, however, has been shown to inhibit malignant B cell proliferation due to their expression of ILT2 surface receptors, which is lacking in solid tumor cells (102,119).…”

Overexpressed immunoglobulin-like transcript (ILT) 4 in lung adenocarcinoma is correlated with immunosuppressive T cell subset infiltration and poor patient outcomes

“…Its expression and functionality in the tumor microenvironment have drawn great attention since last decade. We found that enriched ILT4 expression is the common feature for malignancies including NSCLC, breast cancer, hepatocellular carcinoma and colorectal cancer [11,[24][25][26]. The subsequent investigation from our and other groups demonstrated that tumor cell-derived ILT4 supported tumor growth and metastasis through induction of their malignant behaviors such as proliferation, invasion, migration, EMT and HSC self-renewal [12][13][14]27].…”

Hitting More Birds with a Stone: Impact of TGF-β on ILC Activity in Cancer

“…In gastric cancer cells, TGF-β induces HLA-G expression through miR-152 inhibition, which results in the suppression of NK cell functions mediated by the interaction between HLA-G and the receptor ILT2 [58,59]. In agreement with this evidence, HLA-G induction is guided by TGF-β in ovarian cancer and in pancreatic adenocarcinoma cells where the cytokine increases also the surface levels of HLA-E, the ligand for the NK cell inhibitory receptor NKG2A [60,61].…”