Differential sensitivity to non-major histocompatibility complex-restricted recombinant interleukin 2-activated lymphocyte killing of human mammary epithelial MCF-10A cells overexpressing oncogenes or protein kinase a subunits

Pierosandro Tagliaferri, Giampaolo Tortora, Rosario Guarrasi, Vincenzo Damiano, Angela Ruggiero, Daniela Morelli, Michele Caraglia, Roberto Bianco, Giuditta Di Isernia, Stefano Pepe, Carlos L. Arteaga, Beatrice C. Langten-Webster, A. Raffaele Bianco, Fortunato Ciardiello

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

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 languageEnglish (US)
Pages (from-to)207-214
Number of pages8
JournalClinical Cancer Research
Volume2
Issue number1
StatePublished - Jan 1 1996

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Tagliaferri, P., Tortora, G., Guarrasi, R., Damiano, V., Ruggiero, A., Morelli, D., Caraglia, M., Bianco, R., Di Isernia, G., Pepe, S., Arteaga, C. L., Langten-Webster, B. C., Bianco, A. R., & Ciardiello, F. (1996). Differential sensitivity to non-major histocompatibility complex-restricted recombinant interleukin 2-activated lymphocyte killing of human mammary epithelial MCF-10A cells overexpressing oncogenes or protein kinase a subunits. Clinical Cancer Research, 2(1), 207-214.