Abstract

To create more effective T cells against human tumors, we have designed a strategy to allow T cells to recognize tumor cells using natural killer (NK) cell receptors but retain the effector responses of T lymphocytes. NKG2D is an activating cell surface receptor expressed on NK cells and on some T-cell subsets. Its ligands are primarily expressed on tumor cells. We have shown that by linking mouse NKG2D to the CD3zeta chain, it was possible to generate a chimeric NKG2D (chNKG2D) receptor that allowed activation of murine T cells on engagement with NKG2D ligand-positive tumor cells leading to antitumor responses in mice. In this study, a human version of the chNKG2D receptor was expressed on primary human T cells, and antitumor responses were determined. Human peripheral blood mononuclear cell-derived T cells were retrovirally transduced with a human chNKG2D receptor gene. These chNKG2D-bearing human T cells responded to NKG2D ligand-positive tumor cells by producing T-helper 1 cytokines, proinflammatory chemokines, and significant cellular cytotoxicity. This response could be blocked by anti-NKG2D antibodies, and it was dependent on NKG2D ligand expression on the target cells but not on expression of MHC molecules. In addition, the activity of chNKG2D-bearing T cells remained unimpaired after exposure to a soluble NKG2D ligand, soluble MICA, at concentrations as high as 1.5 mug/mL. These data indicate the feasibility of using chNKG2D receptors in primary human T cells and suggest that this approach may be a promising means for cancer immunotherapy.

Highlights

  • As a part of innate immunity, natural killer (NK) cells play an important role in prevention of tumor growth

  • To determine whether the chimeric NKG2D (chNKG2D) receptor could be expressed in a similar manner as wild-type NKG2D (wtNKG2D), we cotransfected these genes with an adaptor protein gene (Dap10) into Bosc23 cells. wtNKG2D requires Dap10 to be expressed at the cell surface

  • Surface expression of NKG2D was comparable after transfection with chNKG2D to those where the wtNKG2D gene was used

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Summary

Introduction

As a part of innate immunity, natural killer (NK) cells play an important role in prevention of tumor growth. NK cells attack tumors in the absence of MHC restriction using a combination of signals from activating and inhibitory receptors [1, 2]. Adoptive transfer of activated or allogeneic NK cells is effective in treatment of certain types of leukemia and solid tumors [3, 4]. In many cases, NK cell–mediated antitumor responses are weak, which may be due to the expression of inhibitory receptors, poor capacity for survival, or limited migration of effector cells into tumor sites [3, 5, 6]. T cells can migrate efficiently into various tissues and proliferate well in response to antigen stimulation [4, 7].

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