DIFFERENTIAL SENSITIVITY TO NONMAJOR HISTOCOMPATIBILITY COMPLEX-RESTRICTED RECOMBINANT INTERLEUKIN 2-ACTIVATED LYMPHOCYTE KILLING OF HUMAN MAMMARY EPITHELIAL MCF-10A CELLS OVEREXPRESSING ONCOGENES OR PROTEIN-KINASE-A SUBUNITS

The sensitivity of human tumor cells to activated lymphocytes is consi dered to play an essential role in the antitumor activity of recombina nt interleukin-2 (rIL-2)-based immunotherapy, We have investigated the effects of several genes involved in the regulation of cell growth an d transformation on the sensitivity of human mammary epithelial MCF-10 A cells to non-MHC-restricted, rIL-2-activated lymphocytes, Therefore, the lysability of MCF-10A cells overexpressing activated oncogenes (H a-ras, erbB-2, and a mutated p53), growth factors [transforming growth factor alpha (TGF alpha)], or cAMP-dependent protein kinase A subunit s (RI alpha, RII beta, and C alpha) was evaluated comparatively at dif ferent effector:target ratios by a Cr-51 release assay. Parental MCF-1 0A, MCF-10A p53-mutated, and MCF-10A RII beta cells showed an intermed iate sensitivity. Lysability was increased significantly in MCF-10A Ha -ras, MCF-10A TGF alpha, and MCF-10A RI alpha cells, reduced in MCF-10 A C alpha cells, and completely abrogated in MCF-10A erbB-2 cells. The se differences could not be explained by simple changes in the cell su rface expression of MHC class I and intercellular adhesion molecule-1 proteins or by secretion of TGF beta. Treatment with TAb 250, a mouse anti-p185(erbB-2) monoclonal antibody, or down-regulation of p185(erbB -2) expression resulted in circumvention of MCF-10A erbB-2 cell resist ance. We conclude that molecular changes at the single-gene level resu lting in alterations of intracellular signaling and/or cell transforma tion modulate sensitivity of human mammary epithelial cells to non-MHC -restricted, rIL-2-induced cytotoxicity, regardless of MHC class I and /or intercellular adhesion molecule-1 expression or TGF beta secretion , Furthermore, anti-p185(erbB-2) monoclonal antibodies may be useful a s adjuncts to rIL-2 treatment in patients with erbB-2-overexpressing t umors.