Both CD4 and CD8 T cells mediate equally effective in vivo tumor treatment when engineered with a highly avid TCR targeting tyrosinase

Timothy L. Frankel, William R. Burns, Peter D. Peng, Zhiya Yu, Dhanalakshmi Chinnasamy, Jennifer A. Wargo, Zhili Zheng, Nicholas P. Restifo, Steven A. Rosenberg, Richard A. Morgan

Research output: Contribution to journalArticle

Abstract

Tyrosinase, an enzyme involved in melanin synthesis, is expressed in nearly all primary and metastatic melanoma lesions and thus is an attractive target for TCR-based gene therapy using adoptive cell transfer. The TCR α- and β-chain genes from a tumor-infiltrating lymphocyte, which recognized the tyrosinase 368-376 peptide in the context of HLA-A2, were cloned into a γ-retroviral vector. Following transduction of PBL, specific reactivity was confirmed by cytokine production following coculture with tumor targets. Experiments using Ab blockade and CD4/CD8 sorting of the transduced PBLs demonstrated that this antityrosinase TCR was CD4/CD8 independent. The introduction of a second disulfide bond between the TCR constant regions and/or creation of a chimeric protein in which the human constant regions were replaced by murine homologs resulted in enhanced TCR expression as demonstrated by tetramer staining and improved tumor reactivity that was comparable to PBL transduced with either antimelanoma Ag recognized by T cells-1 or anti-gp100 TCR vectors currently used in clinical trials. The chimeric TCR also allowed us to test antitumor function of in HLA-A2/Kb-transgenic mice. Transfer of the antityrosinase TCR into mouse splenocytes conferred CD4/CD8-independent, HLA-A2-restricted Ag reactivity against B16/A2Kb murine melanoma in vitro. Furthermore, adoptive transfer of transduced splenocytes mediated B16/A2Kb melanoma tumor regression in lymphodepleted mice, and , surprisingly, both CD8 and CD4 T cells were equally effective in mediating tumor regression. These results suggest that this highly active tyrosinase-specific TCR could be of value in adoptive cell transfer for melanoma.

Original languageEnglish (US)
Pages (from-to)5988-5998
Number of pages11
JournalJournal of Immunology
Volume184
Issue number11
DOIs
StatePublished - Jun 1 2010

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Frankel, T. L., Burns, W. R., Peng, P. D., Yu, Z., Chinnasamy, D., Wargo, J. A., Zheng, Z., Restifo, N. P., Rosenberg, S. A., & Morgan, R. A. (2010). Both CD4 and CD8 T cells mediate equally effective in vivo tumor treatment when engineered with a highly avid TCR targeting tyrosinase. Journal of Immunology, 184(11), 5988-5998. https://doi.org/10.4049/jimmunol.1000189