title: Cytotoxic T cell targeting of TRP-2 sensitizes human malignant glioma to chemotherapy.
abstract: Tyrosinase-related protein (TRP)-2 is not only expressed on glioma cells, but is naturally processed and presented by their surface MHC molecules and is recognized by TRP-2-specific cytotoxic T cells. After active immunotherapy, we detected TRP-2-specific cytotoxic T lymphocyte (CTL) activity in patients' peripheral blood mononuclear cells (PBMC). Tumor cells from postvaccination resections showed significantly lower TRP-2 expression and higher sensitivity to carboplatin and temozolomide than those autologous cell lines from prevaccination resections in two patients who demonstrated CTL response to TRP-2. One of two patients underwent treatment with temozolomide after recurrence and responded dramatically. TRP-2-transfected cell line (TRP-2-U373) resulted in significant drug resistance to carboplatin and temozolomide compared to wild-type U-373 (W-U373). There was no significant difference, however, in the mRNA expression of other common drug resistance related proteins, such as BCRP-1, MGMT, MDR-1, MRP-1 and MRP-3, after TRP-2 transfection. TRP-2-U373 tumor cells were immunoselected by a TRP-2-specific CTL line. The immunoselected cells (IS-TRP-2-U373) demonstrated significantly increased sensitivity to carboplatin and temozolomide compared to TRP-2-U373. For the first time, we provide evidence that immunological targeting of tumor-associated antigen TRP-2 significantly increases sensitivity to chemotherapy.
authors.affiliation: Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Gentao
authors.initials: G
authors.lastname: Liu
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Akasaki
authors.forename: Hung T
authors.initials: HT
authors.lastname: Khong
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Wheeler
authors.forename: Asha
authors.initials: A
authors.lastname: Das
authors.forename: Keith L
authors.initials: KL
authors.lastname: Black
authors.forename: John S
authors.initials: JS
authors.lastname: Yu
mesh_terms: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000276:immunology* / Q000628:therapy*; D016190:Carboplatin / Q000494:pharmacology; D003131:Combined Modality Therapy; D004249:DNA Damage; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm / Q000276:immunology*; D005910:Glioma / Q000276:immunology* / Q000628:therapy*; D006801:Humans; D016233:Immunotherapy, Active; D019746:Intramolecular Oxidoreductases / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D000077204:Temozolomide; D014162:Transfection; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D003606:Dacarbazine; D016190:Carboplatin; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase; D000077204:Temozolomide