Identification of a T-cell receptor from a therapeutic murine T-cell clone

Joel Shilyansky, James C. Yang, Mary C. Custer, Paul Spiess, Arnold Mixon, David J. Cole, James J. Mulé, Steven A. Rosenberg, Michael I. Nishimura

Research output: Contribution to journalArticle

Abstract

Tumor-infiltrating lymphocytes (TIL) have been successfully used for the treatment of metastatic malignancies in clinical trials and in experimental animal models. Tumor-specific reactivity by TIL is mediated via receptors expressed on the surface of T cells (TcRs), which recognize tumor-associated antigens (TAA) presented in the context of MHC molecules on the surface of tumor cells. The current study was performed to identify the TcR α and β chains from a tumor-specific therapeutic TIL clone that can be used to develop a preclinical animal model for genetically modifying lymphocytes and hematopoietic progenitors with TcR genes. TIL 205 was generated from a subcutaneous implant of MCA-205 fibrosarcoma and at 21 days was cloned by limiting dilution. TIL clone 8, obtained from a culture seeded at one cell/well, mediated specific lysis and specific secretion of γ-interferon to MCA-205 and WP6, a subclone of MCA 205. No reactivity was observed against other syngeneic sarcoma lines. Anchor polymerase chain reaction analysis determined that antigen recognition by clone 8 was mediated by a TcR consisting of Vα3/Jα27 and Vβ8.2/Dβ2.1/Dβ2.4. Immunofluorescent staining with Vβ subfamily specific monoclonal antibodies revealed that >95% of the T cells in TIL clone 8 expressed Vβ8.2, confirming that TIL clone 8 was indeed a clone. In contrast, -30% of the T cells in the parental TIL 205 expressed Vβ8.2. The transfer of as few as 500,000 TIL clone 8 cells in conjunction with the systemic administration of recombinant human interleukin-2 mediated regression of established 3-day WP6 lung metastases. Thus, clone 8 recognizes a biologically relevant tumor rejection antigen, making the Vα3/Jα27- Vβ8.2/Dβ2.1/Jβ2.4 TcR isolated from this clone useful as a probe for cloning the tumor-rejection antigen in the WP6 tumor as well as modeling, in mice, the TcR-based gene therapies being developed for humans.

Original languageEnglish (US)
Pages (from-to)247-255
Number of pages9
JournalJournal of Immunotherapy
Volume20
Issue number4
DOIs
StatePublished - Dec 1 1997

Keywords

  • T-cell clone
  • T-cell receptor

ASJC Scopus subject areas

  • Immunology
  • Pharmacology
  • Cancer Research

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    Shilyansky, J., Yang, J. C., Custer, M. C., Spiess, P., Mixon, A., Cole, D. J., Mulé, J. J., Rosenberg, S. A., & Nishimura, M. I. (1997). Identification of a T-cell receptor from a therapeutic murine T-cell clone. Journal of Immunotherapy, 20(4), 247-255. https://doi.org/10.1097/00002371-199707000-00001