TY - JOUR
T1 - 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
AU - Tagliaferri, Pierosandro
AU - Tortora, Giampaolo
AU - Guarrasi, Rosario
AU - Damiano, Vincenzo
AU - Ruggiero, Angela
AU - Morelli, Daniela
AU - Caraglia, Michele
AU - Bianco, Roberto
AU - Di Isernia, Giuditta
AU - Pepe, Stefano
AU - Arteaga, Carlos L.
AU - Langten-Webster, Beatrice C.
AU - Bianco, A. Raffaele
AU - Ciardiello, Fortunato
PY - 1996/1
Y1 - 1996/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0030061521&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0030061521&partnerID=8YFLogxK
M3 - Article
C2 - 9816108
AN - SCOPUS:0030061521
SN - 1078-0432
VL - 2
SP - 207
EP - 214
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 1
ER -