Capitalizing on the immunogenicity of dying tumor cells

Cancer cell death occurs continually during tumor development and progression, whereas the selective killing of surviving cancer cells remains the primary objective of antineoplastic treatments. Recent insights into the immunologic consequences of cancer cell death have begun to elucidate the ways in which host antitumor immunity is shaped during cancer pathogenesis and then modulated by therapeutic intervention. Dying tumor cells evoke a range of host responses, dependent in part upon the mode of cell death, which may either impede or foster additional immune-mediated cancer destruction. Within the tumor microenvironment, the capture of apoptotic tumor cells by macrophages and dendritic cells may trigger tolerance networks that contribute to immune suppression, whereas the uptake of necrotic cancer cells may engender inflammatory pathways that fuel antitumor cytotoxicity. Milk fat globule epidermal growth factor 8, a phosphatidylserine-binding protein, and MHC class I chain-related protein A, an NKG2D ligand, play key roles in these competing outcomes. A deeper understanding of the mechanisms underlying the immunogenicity of dying cells informs the crafting of strategies that exploit endogenous or treatment-induced cancer cell death as the basis for stimulating sustained host antitumor cytotoxic reactions.