Generation and Targeting of Human Tumor-Specific Tc1 and Th1 Cells Transduced with a Lentivirus Containing a Chimeric Immunoglobulin T-Cell Receptor

Hiroshi Gyobu, Takemasa Tsuji, Yoshinori Suzuki, Takayuki Ohkuri, Kenji Chamoto, Masahide Kuroki, Hiroyuki Miyoshi, You Kawarada, Hiroyuki Katoh, Tsuguhide Takeshima, Takashi Nishimura

Research output: Contribution to journalArticle

51 Scopus citations

Abstract

CD4+ Th cells, in particular IFN-γ-producing Th1 cells, play a critical role in the activation and maintenance of Tc1 cells that are essential for tumor eradication. Here, we report the generation of artificial tumor-specific Th1 and Tc1 cells from nonspecifically activated T cells using a lentiviral transduction system. Anti-CD3-activated T cells from healthy human donors were transduced with a lentivirus containing a chimeric immunoglobulin T-cell receptor gene composed of single-chain variable fragments derived from an anticarcinoembryonic antigen (CEA)-specific monoclonal antibody fused to an intracellular signaling domain derived from the cytoplasmic portions of membrane-bound CD28 and CD3ζ. These artificial tumor-specific Tc1 and Th1 cells, termed Tc1- and Th1-T bodies, respectively, could be targeted to CEA + tumor cells independently of MHC restriction. Specifically, Tc1-T bodies demonstrated high cytotoxicity and produced IFN-γ in response to CEA+ tumor cell lines but not CEA+ tumors. Although Th1-T bodies exhibited low cytotoxicity, they secreted high levels of IFN-γ and interleukin-2 in response to CEA+ tumor cells. Such CEA+ tumor-specific activation was not observed in mock gene-transduced nonspecific Tc1 and Th1 cells. Moreover, Tc1- and Th1-T bodies exhibited strong antitumor activities against CEA+ human lung cancer cells implanted into RAG2-/- mice. Furthermore, combined therapy with Tc1- and Th1-T bodies resulted in enhanced antitumor activities in vivo. Taken together, our findings demonstrate that Tc1- and Th1-T bodies represent a promising alternative to current methods for the development of effective adoptive immunotherapies.

Original languageEnglish (US)
Pages (from-to)1490-1495
Number of pages6
JournalCancer research
Volume64
Issue number4
DOIs
StatePublished - Feb 15 2004

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Gyobu, H., Tsuji, T., Suzuki, Y., Ohkuri, T., Chamoto, K., Kuroki, M., Miyoshi, H., Kawarada, Y., Katoh, H., Takeshima, T., & Nishimura, T. (2004). Generation and Targeting of Human Tumor-Specific Tc1 and Th1 Cells Transduced with a Lentivirus Containing a Chimeric Immunoglobulin T-Cell Receptor. Cancer research, 64(4), 1490-1495. https://doi.org/10.1158/0008-5472.CAN-03-2780