Cytotoxic effects of γδ T cells expanded ex vivo by a third generation bisphosphonate for cancer immunotherapy

Abstract

Nitrogen containing-bisphosphonates (N-BPs), widely used to treat bone diseases, have direct antitumor effects via the inactivation of Ras proteins. In addition to the direct antitumor activities, N-BPs expand gdT cells, which exhibit major histocompatibility complex-unrestricted lytic activity. BPs accumulate intermediate metabolites which may be tumor antigens in target cells. The purpose of our study was to clarify the cytotoxicity of gd T cells expanded ex vivo by the most potent N-BP, zoledronate (ZOL). Especially, we focused on the importance of pretreatment against target cells also with ZOL; 1 mM ZOL plus IL-2 increased the absolute number of gdT cells 298-768 fold for 14 days incubation. The small cell lung cancer and fibrosarcoma cell lines pretreated with 5 mM ZOL showed a marked increase in sensitivity to lysis by gdT cells. While, untreated cell lines were much less sensitive to lysis by gdT cells. Video microscopy clearly demonstrated that gdT cells killed target cells pre-treated with ZOL within 3 hr. Pretreatment with 80 mg/kg ZOL also significantly enhanced the antitumor activity of gdT cells in mice xenografted with SBC-5 cells. These findings show that ZOL significantly stimulated the proliferation of gdT cells and that gdT cells required pre-treatment with ZOL for cytotoxic activity against target cells. ' 2005 Wiley-Liss, Inc.

Vγ9Vδ2 T cell cytotoxicity against tumor cells is enhanced by monoclonal antibody drugs—Rituximab and trastuzumab

“…1,2 Evidence that Vg9Vd2 T cells have potent cytotoxic activity against tumor cells in a non-MHCrestricted manner in vitro [3][4][5][6] raise the possibility that Vg9Vd2 T cells could be utilized as a component of antitumor therapies. [7][8][9][10][11] After their activation by nonpeptidic phosphoantigens via gd TCR binding, Vg9Vd2 T cells can recognize and exert cytotoxicity against tumor cells in various ways.…”

DNAX accessory molecule‐1 (CD226) promotes human hepatocellular carcinoma cell lysis by Vγ9Vδ2 T cells

“…Immunological approaches using innate antitumor effector cells are currently being evaluated in clinical trials [2]. Vg9Vd2 T cells represent the major population of human peripheral blood gd T cells and display an in vitro non-MHCrestricted lytic activity against a broad panel of tumors including colon, kidney, liver, esophageal, small-lung cancers and myeloma [3][4][5][6][7][8][9]. The presence of tumor-infiltrating Vd2 1 T cells in tumorbearing livers of patients may support their potential role in tumor immunosurveillance of HCC [10].…”

“…Vg9Vd2 T cells recognize small nonpeptidic phosphorylated antigens such as isopentenyl pyrophosphate produced in mammalian cells through the mevalonate pathway [11]. Aminobisphosphonate such as zoledronate may activate Vg9Vd2 T cells indirectly by blocking the mevalonate pathway and consequently promoting intracellular accumulation of isopentenyl pyrophosphate [8]. Recent findings suggest that the mitochondrial F1-ATPase exposed at the surface of the stimulating cells could participate to phosphoantigen presentation and subsequent Vg9Vd2 T-cell activation [12,13].…”

A third-generation bisphosphonate, minodronic acid (YM529), successfully prevented the growth of bladder cancer in vitro and in vivo

“…Bisphosphonates inhibit farnesyl pyrophosphate synthase, which is part of the mevalonate pathway. Consequently, BPs inhibit the activation of small G-proteins such as Ras, Rap1, and Rho, and reduce the signals necessary for cancerous progressions, which are transduced by these proteins (Kuroda et al, 2003;Nogawa et al, 2005b;Sato et al, 2005;Yuasa et al, 2005).…”