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Non-small cell lung cancer (NSCLC) is the most common malignant tumor in the world, of which prognosis is generally poor due to insufficient mechanistic understanding. To explore the molecular pathogenesis of NSCLC, the co-expression of immunoglobulin-like transcript 4 (ILT4) and its ligand human leukocyte antigen G (HLA-G) in NSCLC tissues and cells were investigated. Here, we detected the expression of ILT4 and HLA-G in 81 tumor specimens from primary NSCLC patients, and we found that co-expression of ILT4/HLA-G was significantly associated with regional lymph node involvement, advanced stages, and the overall survival of patients. In NSCLC cell lines, HLA-G expression increased/decreased accordingly when ILT4 was up-/down-regulated, and ILT4 expression increased in a concentration-dependent manner via the stimulation of HLA-G fusion protein. Interestingly, HLA-G fusion protein could also up-regulate the phospho-ERK1/2 expression, which means the activation of extracellular signal-regulated kinase (ERK) signaling. All in all, our results indicate that the ILT4-HLA-G interaction might play an important role in NSCLC progression. Identification of ILT4 and HLA-G expression may provide an indicator to predict prognosis and guide prevention and treatment of NSCLC.

The functional phenotypes (M1 and M2) of tumor-associated macrophages (TAMs) are influenced by the tumor microenvironment (TME) and contribute greatly to the development of non-small cell lung cancer (NSCLC). However, the molecular mechanisms for TAM polarization remain unclear. Angiopoietin-like protein 2 (Angptl2) is involved in tumor progression. In this study, Angptl2 expression was aberrantly increased in NSCLC cells and positively correlated with TAM infiltration, tumor size and poor patient survival. Moreover, in vitro tumor cell-macrophage co-culture and recombinant protein stimulation revealed that Angptl2 fostered the M2 polarization of TAMs through the p65 nuclear factor-kappa B (NF-ĸB) pathway. In addition, Angptl2-promoted TAM enhanced proliferation, invasion, and migration of NSCLC cells and the tube formation of human umbilical vein endothelial cells (HUVECs). In vivo, TAM depletion inhibited the tumor growth induced by Angptl2. Here, for the first time, we determined that Angptl2 promoted the M2 polarization of TAMs and enhanced NSCLC progression. Interfering with Angptl2 might be an effective strategy for reprogramming TAM polarization in NSCLC, providing a promising therapy for NSCLC treatment.