Indeed, a study using a human lung adenocarcinoma cell line revealed that tumor cell-derived osteopontin regulates M2 polarization by the up-regulation of programmed cell death-ligand 1 (PD-L1) on macrophages, and osteopontin knockdown results in macrophages with increased CD4+ T cell activation capacity [144]. Here, SPP1 is linked to lung adenocarcinoma.