Integrin β8 Facilitates Macrophage Infiltration and Polarization by Regulating CCL5 to Promote LUAD Progression

Abstract The tumor microenvironment (TME) influences cancer progression and metastasis. Integrin β 8 (ITG β 8), a member of the integrin family, is upregulated in various cancers. In this study, it is determined as a key factor that mediates the interaction between lung adenocarcinoma (LUAD) cells and macrophages. Increased expression levels of ITG β 8 are associated with increased numbers of CD163+ macrophages and poor prognosis in LUAD patients. The overexpression of ITG β 8 in LUAD cells promotes the polarization of THP‐1 macrophages toward the M2 phenotype. In contrast, TCM (conditioned medium from the co‐culture system) from THP‐1 macrophages and ITG β 8‐overexpressing A549 cells promoted the proliferation and invasion of A549 cells. Mechanistically, chemokine (C‐C motif) ligand 5 (CCL5) plays an important role in mediating ITG β 8‐induced macrophage polarization, and the phosphoinositide 3‐kinase (PI3K)/AKT serine/threonine kinase (AKT)/interferon regulatory factor 9 (IRF9) pathway is involved in this process. Moreover, interleukin 8 (IL8) and interleukin 10 (IL10) produced by M2‐like macrophages regulate the expression of ITG β 8 in LUAD cells through the spi‐1 proto‐oncogene (SPI1). This study elucidates the feedback mechanism of ITG β 8 between LUAD cells and macrophages.