| Summary: | Abstract Background Human endogenous retrovirus‐H long terminal repeat‐associating protein 2 (HHLA2) is a member of B7 family, which is upregulated in multiple tumors. However, its exact functions in non‐small cell lung cancer (NSCLC) have not been fully understood. This study aimed to investigate the biological roles of HHLA2 in human NSCLC and the relevant mechanisms. In addition, the effects of tumor cell‐derived HHLA2 on tumor‐associated macrophage (TAM) polarization were explored. Methods NSCLC cell growth, migration, and invasion were assessed by colony formation and modified Boyden chamber assays. Cell cycle and the CD163+ TAMs were examined by flow cytometry. A co‐culture model of THP‐1 macrophages and NSCLC cells was conducted to investigate the impacts of tumor cell‐derived HHLA2 on THP‐1 macrophage polarization. Moreover, a xenograft nude mouse model was established to explore the effects of HHLA2 on tumorigenesis in vivo. Results HHLA2 was upregulated in A549 and H1299 cells compared with the normal lung epithelial BEAS‐2B cells. HHLA2 deficiency inhibited NSCLC cell proliferation, migration, invasion, and induced G0/G1 phase arrest partially via inhibiting EGFR/MAPK/ERK signaling pathway. Furthermore, HHLA2 knockdown inhibited M2 polarization of TAMs via downregulating IL‐10. In addition, knockdown of HHLA2 inhibited tumor growth in vivo. Conclusion HHLA2 downregulation inhibited NSCLC growth and TAM M2 polarization. HHLA2 may serve as a therapeutic target and promising prognostic biomarker in NSCLC.
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