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

• Hiroshi Gyobu

  1Division of Immunoregulation, Institute for Genetic Medicine and

• Takemasa Tsuji

  1Division of Immunoregulation, Institute for Genetic Medicine and

• Yoshinori Suzuki

  1Division of Immunoregulation, Institute for Genetic Medicine and

• Takayuki Ohkuri

  1Division of Immunoregulation, Institute for Genetic Medicine and

• Kenji Chamoto

  1Division of Immunoregulation, Institute for Genetic Medicine and

• Masahide Kuroki

  3First Department of Biochemistry, Fukuoka University School of Medicine, Fukuoka; and

• Hiroyuki Miyoshi

  4Subteam for Manipulation of Cell Fate, BioResource Center, RIKEN Tsukuba Institute, Ibaraki Japan

• You Kawarada

  2Surgical Oncology, Cancer Medicine, Division of Cancer Medicine, Hokkaido University, Sapporo;

• Hiroyuki Katoh

  2Surgical Oncology, Cancer Medicine, Division of Cancer Medicine, Hokkaido University, Sapporo;

• Tsuguhide Takeshima

  1Division of Immunoregulation, Institute for Genetic Medicine and

• Takashi Nishimura

  1Division of Immunoregulation, Institute for Genetic Medicine and

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.

Journal

• Cancer Research

  Cancer Research 64 (4), 1490-1495, 2004-02-15

  American Association for Cancer Research (AACR)

Keywords

• Cancer Research
• Oncology

Details

• CRID: 1363951793434280192
• NII Article ID: 30018589908
• DOI: 10.1158/0008-5472.can-03-2780
• ISSN: 15387445
• ISSN: 00085472
• ISSN: http://id.crossref.org/issn/00085472
• Web Site: https://aacrjournals.org/cancerres/article-pdf/64/4/1490/2522552/zch00404001490.pdf
• Data Source:
  • Crossref
  • CiNii Articles