The sensitivity of human tumor cells to activated lymphocytes is considered to play an essential role in the anti-tumor activity of recombinant interleukin-2 (rIL-2)-based immunotherapy. We have investigated the effects of several genes involved in the regulation of cell growth and transformation on the sensitivity of human mammary epithelial MCF-10A cells to non-MHC-restricted, rIL-2-activated lymphocytes. Therefore, the lysability of MCF-10A cells overexpressing activated oncogenes (Ha-ras, erbB-2, and a mutated p53), growth factors [transforming growth factor α (TGFα)], or cAMP-dependent protein kinase A subunits (RIα, RIIβ, and Cα) was evaluated comparatively at different effector:target ratios by a 51Cr release assay. Parental MCF-10A, MCF-10A p53-mutated, and MCF-10A RIIβ cells showed an intermediate sensitivity. Lysability was increased significantly in MCF-10A Ha-ras, MCF-10A TGFα, and MCF-10A RIα cells, reduced in MCF-10A Cα cells, and completely abrogated in MCF-10A erbB-2 cells. These differences could not be explained by simple changes in the cell surface expression of MHC class I and intercellular adhesion molecule-1 proteins or by secretion of TGFβ. Treatment with TAb 250, a mouse anti-pl85erbB-2 monoclonal antibody, or down-regulation of p185erbB-2 expression resulted in circumvention of MCF-10A erbB-2 cell resistance. We conclude that molecular changes at the single-gene level resulting in alterations of intracellular signaling and/or cell transformation 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 TGFβ secretion. Furthermore, anti-p185erbB-2 monoclonal antibodies may be useful as adjuncts to rIL-2 treatment in patients with erbB-2-overexpressing tumors.
|Original language||English (US)|
|Number of pages||8|
|Journal||Clinical Cancer Research|
|State||Published - Jan 1 1996|
ASJC Scopus subject areas
- Cancer Research