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Cytotoxic T cell targeting of TRP-2 sensitizes human malignant glioma to chemotherapy

Oncogene volume 24, pages 5226–5234 (2005)Cite this article

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.

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Acknowledgements

We thank Dr W Robert Bishop, Schering-Plough Research Institute for providing the temozolomide; Dr Vincent J Hearing, National Cancer Institute, NIH for providing the TRP-2 antibody; Dr Shigeki Shibahara, Tohoku University School of Medicine, Japan for providing the TRP-2 expression plasmid, and Dr Scot MacDonald for editorial assistance. This work was supported in part by NIH Grant K23 NS02232.

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Authors and Affiliations

  1. Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, 90048, CA, USA

    Gentao Liu, Yasuharu Akasaki, Christopher J Wheeler, Asha Das, Keith L Black & John S Yu

  2. University of South Alabama Cancer Research Institute, Mobile, 36688, AL, USA

    Hung T Khong

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  1. Gentao Liu
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  2. Yasuharu Akasaki
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Correspondence to John S Yu.

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Liu, G., Akasaki, Y., Khong, H. et al. Cytotoxic T cell targeting of TRP-2 sensitizes human malignant glioma to chemotherapy. Oncogene 24, 5226–5234 (2005). https://doi.org/10.1038/sj.onc.1208519

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