p53-dependent chemokine expression by tumor cells supports NKG2D-dependent elimination of senescent tumors by natural killer cells (P2115)

Abstract The cellular senescence is a key mechanism by which p53 suppresses tumorigenesis. Using a mouse model in which p53 expression can be regulated in tumor cells, we confirmed that NK cells participate in the elimination of senescent tumors. We further demonstrate that tumor elimination is dependent on the function of NKG2D. Surprisingly, however, p53 induction did not increase the expression of any of the NKG2D ligands. Furthermore, tumor cells grown in vitro were sensitive to NK lysis, in an NKG2D-dependent fashion, but p53 induction did not increase the sensitivity of the cells to NK lysis. Instead, our data demonstrate that p53 restoration enhanced the recruitment of NK cells into the tumor. We found that p53 restoration in vitro and in vivo induced the secretion of various chemokines and cytokines. Among the chemokines induced in senescent tumor cells was CCL2. Blockade of CCL2 in vivo with antibodies inhibited NK cell recruitment to the tumor and reduced the rate of elimination of the senescent tumors. Our findings suggest that expression of NKG2D ligands occurs largely independently of p53 or senescence, but that recruitment of NK cells to the tumor, and consequently the efficient elimination of the tumor by NK cells, is dependent on chemokine expression associated with the induction of senescence. Thus, p53-induced immune cell recruitment acts cooperatively with other signals in tumor cells that induce NKG2D ligands to promote the elimination of tumors.