Table 3.

Classification of immunomodulatory strategies for improving the killing effectiveness of adoptive NK cell transfer therapy against osteosarcoma.

Immunomodulatory strategy		Mechanism	Study type	Comment
Epigenetic drug	VPA	Augmented expression of MICA/B on tumor cells	Ex vivo	VPA sensitized human osteosarcoma cells to cytotoxicity of NK cells (62)
	Entinostat	Augmented expression of MICA/B, ULBP, and CD155 on tumor cells	In vivo	Entinostat failed to augment the efficacy of NK cell therapy in a nude mouse model of human osteosarcoma lung metastasis (63)
	Entinostat	Downregulation of the anti-apoptotic protein, c-FLIP, and increased levels of Fas within the membrane lipid rafts on tumor cells	Ex vivo	Entinostat sensitized osteosarcoma cells to NK cell-mediated apoptosis (64)
	VPA+ hydralazine	Augmented expression of MICA/B and Fas on tumor cells	Ex vivo	VPA combined with hydralazine enhanced the susceptibility of osteosarcoma cells to Fas- and NK cell-mediated cell death (65)
Cytokine	IL-15	Enhanced DNAM-1 and NKG2D signaling pathways	Ex vivo	IL-15 enhanced cytolytic activity against chemotherapy-resistant osteosarcoma cells (60)
	IL-15	Prevention of down-regulation of NKG2D on NK cells	Ex vivo	IL-15 reversed inhibition of NK cell-mediated cytolytic activity against osteosarcoma (66)
	IL-12+IFN-γ+IL-18	Enhanced expression of ICAM-I on HOS cells	Ex vivo	IL-12 enhanced NK-mediated cytolysis of HOS cells in the presence of IFN-γ and with IL-18 (67)
	IL-12+IL-2	Increased density of CD18 and CD2 molecules on NK cells	Ex vivo	A combination of IL-12 and IL-2 increased lytic activity against and binding to osteosarcoma cells (68)
	IL-17	Increased expression of fibronectin on U2 OS cells	Ex vivo	IL-17 enhanced NK cell-mediated adhesion and cell lysis activity against osteosarcoma (69)
Monoclonal antibody	Cetuximab	ADCC	Ex vivo	Cetuximab augmented cytolytic activity of resting NK cells, which was specifically directed toward osteosarcoma cells (70)