Programming of macrophages by UV-irradiated apoptotic cancer cells inhibits cancer progression and lung metastasis

Apoptotic cell clearance by phagocytes is essential in tissue homeostasis. We demonstrated that conditioned medium (CM) from macrophages exposed to apoptotic cancer cells inhibits the TGF beta 1-induced epithelial-mesenchymal transition (EMT), migration, and invasion of cancer cells. Apoptotic 344SQ (ApoSQ) cell-induced PPAR gamma activity in macrophages increased the levels of PTEN, which was secreted in exosomes. Exosomal PTEN was taken up by recipient lung cancer cells. ApoSQ-exposed CM from PTEN knockdown cells failed to enhance PTEN in 344SQ cells, restore cellular polarity, or exert anti-EMT and anti-invasive effects. The CM that was deficient in PPAR gamma ligands, including 15-HETE, lipoxin A4, and 15d-PGJ2, could not reverse the suppression of PPAR gamma activity or the PTEN increase in 344SQ cells and consequently failed to prevent the EMT process. Moreover, a single injection of ApoSQ cells inhibited lung metastasis in syngeneic immunocompetent mice with enhanced PPAR gamma/PTEN signaling both in tumorassociated macrophages and in tumor cells. PPAR gamma antagonist GW9662 reversed the signaling by PPAR gamma/PTEN; the reduction in EMT-activating transcription factors, such as Snai1 and Zeb1; and the antimetastatic effect of the ApoSQ injection. Thus, the injection of apoptotic lung cancer cells may offer a new strategy for the prevention of lung metastasis.