title: 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.
abstract: The sensitivity of human tumor cells to activated lymphocytes is considered to play an essential role in the antitumor 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 alpha (TGFalpha)], or cAMP-dependent protein kinase A subunits (RIalpha, RIIbeta, and Calpha) was evaluated comparatively at different effector:target ratios by a 51Cr release assay. Parental MCF-10A, MCF-10A p53-mutated, and MCF-10A RIIbeta cells showed an intermediate sensitivity. Lysability was increased significantly in MCF-10A Ha-ras, MCF-10A TGFalpha, and MCF-10A RIalpha cells, reduced in MCF-10A Calpha 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 TGFbeta. 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 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 TGFbeta secretion. Furthermore, anti-p185(erbB-2) monoclonal antibodies may be useful as adjuncts to rIL-2 treatment in patients with erbB-2-overexpressing tumors.
authors.affiliation: Cattedra di Oncologia Medica, Dipartimento di Endocrinologia ed Oncologia Molecolare e Clinica, Università di Napoli "Federico II," via S. Pansini, 5 80131 Naples, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Tagliaferri
authors.forename: G
authors.initials: G
authors.lastname: Tortora
authors.forename: R
authors.initials: R
authors.lastname: Guarrasi
authors.forename: V
authors.initials: V
authors.lastname: Damiano
authors.forename: A
authors.initials: A
authors.lastname: Ruggiero
authors.forename: D
authors.initials: D
authors.lastname: Morelli
authors.forename: M
authors.initials: M
authors.lastname: Caraglia
authors.forename: R
authors.initials: R
authors.lastname: Bianco
authors.forename: G
authors.initials: G
authors.lastname: di Isernia
authors.forename: S
authors.initials: S
authors.lastname: Pepe
authors.forename: C L
authors.initials: CL
authors.lastname: Arteaga
authors.forename: B C
authors.initials: BC
authors.lastname: Langton-Webster
authors.forename: A R
authors.initials: AR
authors.lastname: Bianco
authors.forename: F
authors.initials: F
authors.lastname: Ciardiello
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D003602:Cytotoxicity, Immunologic; D005260:Female; D018734:Genes, erbB-2; D015395:Histocompatibility Antigens Class I / Q000032:analysis; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D007376:Interleukin-2 / Q000494:pharmacology*; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology; D008214:Lymphocytes / Q000276:immunology*; D051379:Mice; D011994:Recombinant Proteins / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D014407:Tumor Cells, Cultured
chemical_list: D015395:Histocompatibility Antigens Class I; D007376:Interleukin-2; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D018799:Intercellular Adhesion Molecule-1; D017868:Cyclic AMP-Dependent Protein Kinases