Abstract 4586: PLAG enhances macrophage mobility for efferocytosis of active neutrophils via membrane redistribution of P2Y2

Neutrophil activity is prerequisite during chemotherapy. The DAMP (Damage Associated Molecular Pattern) molecules generated by chemotherapy could be effectively trapped by activated neutrophil called ‘NETosis’. Efferocytosis of macrophages should remove most activated neutrophils including NETosis A timely removal of activated neutrophils is essential for the prevention of abnormal activation of immune response and metastatic activity of cancer cells induced by tumor microenvironment (TME). Particularly, appropriate clearance of the activated neutrophils by efferocytosis should be carried out because activated neutrophils have a detrimental effect on TME. In this research, we investigated the effect of 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) on efferocytosis and its underlying molecular mechanisms. In a co-culture of activated neutrophils with macrophages, PLAG increased the activity of efferocytosis for elimination of activated neutrophils. PLAG accelerated translocation of P2Y2 from lipid rafts to non-lipid-raft plasma membrane domains in macrophages. This repositioning of P2Y2 enables the polarization of the cytoskeleton by association of the receptor with cytoskeletal proteins such as α-tubulin and actin to improve the mobility of macrophages. Through these protein assemble, PLAG encouraged macrophage mobility toward the activated neutrophils. Formation of micelle including PLAG, chylomicron-like structures, was a prerequisite for induction of this macrophage activity. PLAG effect on this activity was not observed in the absence of GPIHBP1, micelle receptor. Taken together, these data showed that PLAG triggered a prompt clearance of activated neutrophils through enhancement of efferocytosis activity. Subsequently, PLAG could have effects on modulation of TME. PLAG could be utilized as an effective lipid-based TME modulator via the prevention of abnormal activation induced by uncontrolled immune response during chemotherapy. Citation Format: Guen Tae Kim, Do Young Lee, Ki-young Sohn, Sun Young Yoon, Jae Wha Kim. PLAG enhances macrophage mobility for efferocytosis of active neutrophils via membrane redistribution of P2Y2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4586.