NUCLEOSOME-DEPENDENT ESCAPE OF TUMOR-CELLS FROM NATURAL-KILLER-MEDIATED LYSIS - NUCLEOSOMES ARE TAKEN UP BY TARGET-CELLS AND ACT AT A POSTCONJUGATION LEVEL

Our previous data suggested that chromatin fragments released from dea d cells into the extracellular medium could be involved in the impairm ent of natural-killer (NK)-mediated cytotoxicity reported in cancer pa tients. In the present study, an inhibition of the NK-mediated lysis w as obtained in vitro by nucleosome addition to different tumor target cells, independently of their sensitivity to NK-mediated lysis. We obs erved a rapid endocytosis and degradation of nucleosomes by K562 tumor target cells and (although to a much lesser extent) a binding to a su bpopulation of lymphocytes. Nucleosomes impaired neither the conjugati on step nor the expression of adhesion molecules at the effector (CD11 a, CD18, CD2) or target (CD54, CD58) cell surface. On the contrary, fl owcytometry analysis of the conjugation suggested that nucleosomes mig ht stabilize the conjugates. Investigations of the killing process sho wed that nucleosomes decreased the NK cytotoxic potential without modi fying Ca2+-dependent lethal-hit-delivery kinetics. The cytotoxic poten tial was not restored by increasing the available magnesium and calciu m concentrations in the extracellular medium. Taken together, the resu lts suggest that the inhibition of NK-mediated lysis by nucleosomes ma y result from alterations of the NK mechanism at the postconjugation l evel and after lethal-hit delivery. Hence, the inhibition could involv e a delay in the recycling of effector cells, or a resistance of tumor target cells to NK cells.