title: Treatment with HER-2 phosphorylation agonists enhance tumor ability to stimulate epitope specific CTL in vitro.
abstract: The transmembrane (TM) receptor encoded by the HER-2 proto-oncogene (HER-2) is amplified in several types of human carcinomas and premalignant states and provides an important target for cancer therapy. While overexpression of HER-2 should lead to increased CTL epitope formation due to the attendant increase in higher protein turnover, breast tumors are poor stimulators of CTL. In this report, we show that treatment of SKBR3.A2 tumor cells with HER-2 receptor agonists (EGF and NDF) enhanced tumor ability to activate CTL from tumor associated lymphocytes (TAL) and from T cells from peripheral blood in vitro. The enhanced ability of tumor cells to stimulate CTL was paralleled by tyrosine phosphorylation of HER-2, and its oligo-ubiquitination compared with control untreated, or TPA-treated tumor cells. Our results demonstrate that HER-2 ligands used at concentrations which induce tyrosine phosphorylation but not downregulation of the receptor can be used to enhance the ability of tumor cells to activate CTL. This may have implications for overcoming Ag ignorance and tolerance in human cancers.
authors.affiliation: Department of Gynecologic Oncology, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Agapito
authors.initials: A
authors.lastname: Castilleja
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Ward
authors.forename: Richard B
authors.initials: RB
authors.lastname: Epstein
authors.forename: Andrzej P
authors.initials: AP
authors.lastname: Kudelka
authors.forename: David M
authors.initials: DM
authors.lastname: Gershenson
authors.forename: Clay L
authors.initials: CL
authors.lastname: Efferson
authors.forename: Catherine A
authors.initials: CA
authors.lastname: O'Brian
authors.forename: Constantin G
authors.initials: CG
authors.lastname: Ioannides
mesh_terms: D017951:Antigen Presentation; D015153:Blotting, Western; D003602:Cytotoxicity, Immunologic; D000939:Epitopes; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D006801:Humans; D015151:Immunoblotting; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D016246:Lymphocytes, Tumor-Infiltrating / Q000378:metabolism; D010053:Ovary / Q000166:cytology; D010766:Phosphorylation; D011233:Precipitin Tests; D017434:Protein Structure, Tertiary; D000090063:Proto-Oncogene Mas; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism*; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D000939:Epitopes; D018984:Epitopes, T-Lymphocyte; D000090063:Proto-Oncogene Mas; D018719:Erb-b2 Receptor Tyrosine Kinases; D014443:Tyrosine; D025801:Ubiquitin; C000715470:MAS1 protein, human