No abstract

In human melanoma, activation of the c-myc oncogene results in locus-specific down-modulation of the HLA-B antigen expression. Moreover, overexpression of c-myc induces an increase of natural killer (NK) sensitivity of the tumor cells. To show that this effect on susceptibility to NK cells is mediated by the down-modulation of the HLA-B expression rather than by the activation of the oncogene, we supertransfected a c-myc transfectant with the gene encoding the HLA-B27 protein. The resulting supertransfectants with HLA-B27 surface expression were all less sensitive to NK cells than their parental cell line and showed a level of resistance equal to the original melanoma cell line with low c-myc expression. This indicates that the induction of NK sensitivity by c-myc activation in human melanoma cells is mediated through down-modulation of the HLA-B expression. These data also imply differential effects of HLA-A and HLA-B molecules on lysis by NK cells, because the level of NK susceptibility can apparently be defined by the level of HLA-B, irrespective of a substantial level of HLA-A expression present in the tumor cells.

SUMMARYWe have isolated tumour-infiltrating lymphocytes (TIL) clones from a patient wilh renal cell cancer. The cloning frequency and the effector function were measured. No difference in cloning frequency (H = 0-97, frequency = 1: i3) was observed between TIL expanded with ailogeneic rt'r^w.s autologous feeder cells. Sixty-four clones expanded with aulologous feeder eells and 37 clones expanded with allogeneic feeder cells were assayed for cytolytie activiiy on an autologous primary renai cell carcinoma (RCC) culture, an allogeneic RCC line, and on the K562 and Daudi cell lines. Most of these elones were also phenolyped. Although TIL clones expressing cytotoxie activity for RCC lines could be generated with both feeder cell preparations, none of the clones tested showed specificity for ceils from autologous primary RCC cultures. However, in the presence of relevant bispecific MoAbs (aOC/TR) all CDX' TIL clones tested could be induced to Iyse aulologous RCC cultures. Furthermore, the cytolytie activity of all CD8' clones tested against allogeneic RCC lines could be induced or furlher enhanced by aOC/TR or CD3/G250 bispeeific MoAbs. In contrast, none of the CD4' clones tested showed lytic activity. Quantitatively the eyloloxic response in the presence of «OC/TR or CD3/G250 of CD8^ TIL clones against G25O^ and MOvlS* cell lines appears to be associated with ihe level of antigen expression on [he target cells. Our results suggest thai; (i) expansion of TIL wilh allogeneic or aulologous feeder cells does not elTeet the lytic prolilc of the clones; (ii) the use of bispecific MoAbs may overcome a lack of specificity of eytotoxic T lymphocytes.