A central role for death receptor-mediated apoptosis in the rejection of tumors by NK cells

NK cells provide a line of defense against tumors and virus-infected cells that have lost the expression of one or more MHC class I isoforms. Here, we investigate whether inhibitors of apoptosis can block the rejection of tum ors mediated by NK cells, by introducing the long form of Fas-associated de ath domain-like IL-1 beta -converting enzyme-associated inhibitory protein (FLIPL) and poxvirus cytokine response modifier A (CrmA) into the MHC class I-deficient T lymphoma cell line RMA-S. RMA-S cells do not normally expres s Fas in vitro, and it was previously postulated that the rejection of thes e tumors by NK cells is strictly perforin dependent. We show that perforin- deficient NK cells directly mediate Fas up-regulation on RMA-S cells and th ereafter kill the cells in a Fas-dependent manner, and that RMA-S FLIPL and RMA-S CrmA are protected from such killing. When injected in immunocompete nt recipients, RMA-S cells up-regulate Fas, rendering in vivo-passed mock-t ransduced cells sensitive to Fas-mediated apoptosis. Moreover, RMA-S FLIPL and RMA-S CrmA cells establish aggressive tumors, in contrast to RMA-S mock cells that are rejected. These results demonstrate that FLIPL and CrmA fun ction as tumor progression factors by protecting MHC class I-deficient tumo rs from rejection mediated by NK cells. Moreover, our data indicate that de ath receptor-mediated apoptosis has a more prominent role in the clearance of NK-sensitive tumors than previously suggested.