INFLUENCE OF MALIGNANT-CELL CLONOGENIC CAPACITIES AND POSITION ALONG THE MATURATION PATHWAY ON THEIR SUSCEPTIBILITY TO LYMPHOKINE-ACTIVATEDKILLER-CELL CYTOTOXICITY

In order to investigate the sensitivity of malignant target cells to l ysis by LAK cells according to their clonogenic capacities and their p osition along the maturation pathway, we compared clonogenic and chrom ium release cytotoxicity assays performed on human hematopoietic cell Lines using Effector: Target ratios of 1:1, 3:1, 6:1, 12:1, 24:1, 48:1 and 96:1, and studied the sensitivity of HL-60 and U937 human cell li nes after exposure to different factors including GM-CSF, SCF, IFN, Re tinoic acid (RA), DMSO, and TPA which are able to recruit cells into t he cell cycle or to induce cell differentiation. There was a good corr elation between the lysis of the target cells using Cr-51 release and the growth inhibition in semisolid medium. The degree of inhibition wa s significantly higher using the colony growth assay (p = 0.006). Rega rding the effects of culturing cell lines with proliferating and diffe rentiating agents on the sensitivity of these cell lines to LAK cytoly sis, a correlation was noted between the proliferative response of the U937 cell line and susceptibility to LAK cell lysis (p = 0.01), while results appeared close to significance with HL-60. The most significa nt effects were a decreased sensitivity of HL-60 to LAK lysis with RA (p < 0.001) and TPA (p < 0.001), and an increased susceptibility of U9 37 to LAK lysis with GM-CSF (p < 0.0001). In studies planned to invest igate whether susceptibility of treated cells to LAK activity was a co nsequence of a downregulation of adhesion molecules expressed on targe t cell surface, the proportion of cells expressing adhesion molecules was not significantly changed, except for CD54 expression on HL-60 cel ls which showed a higher expression, after cells were treated with RA or DMSO. We conclude that clonogenic cells are more sensitive to LAK c ell lysis and that cell line sensitivity to LAK cytolysis can be modul ated by a variety of agents of potential therapeutic use. The poor cor relation between adhesion molecules expression and sensitivity to LAK lysis suggests that molecules other than CD54, CD56, CD58, and CD106 m ay possibly be more central to the processes involved.