Biomedical subjects

Richard D Lopez

Publications and source records attributed to Richard D Lopez.

5 recordsLinked to original sources

PubMed2005

Innate anti-breast cancer immunity of apoptosis-resistant human gammadelta-T cells.

We previously identified a CD2-initiated signaling pathway which inhibits activation-induced cell death in mitogen-stimulated human gammadelta-T cells permitting the large-scale expansion of these cells. Here we report the innate anti-tumor activity of expanded human gammadelta-T cells against human breast cancer cells. Apoptosis-resistant human gammadelta-T cells which were expanded in vitro from cultured human peripheral blood mononuclear cells displayed lytic activity against breast cancer cell lines MDA-MB-231, MCF-7 and T-47D, but failed to kill normal human skin fibroblasts and normal human liver cells. Monoclonal antibodies (mAb) directed against the gammadelta-T cell receptor (TCR) or mAb directed against either the Vgamma9 or the Vdelta2 TCR chains were able to block gammadelta-T cell-mediated lysis of MDA-MB-231 cells. In addition, mAb against intercellular adhesion molecules-1 (ICAM-1/CD54) or CD18 (beta subunit of ICAM-1 counter-receptor) also blocked gammadelta-T cell-mediated killing of MDA-MB-231 cells. Ex vivo expanded human gammadelta-T cells are thus able to innately recognize and kill human breast cancer cells in a gammadelta-TCR-dependent manner; ICAM-1 and CD18 also appear to be involved in the interactions between sensitive breast cancer cells and cytolytic gammadelta-T cells. As apoptosis-resistant human gammadelta-T cells can now readily be expanded to large numbers (clinical scale), these findings must be considered in the context of developing adoptive immunotherapy strategies to exploit gammadelta-T cell innate immune responses for the primary or adjuvant treatment of breast cancer.

Apoptosis↗

PubMed2005

gammadelta T cells: a new frontier for immunotherapy?

The use of cytolytic effector cells as therapy for malignant disease has been a central focus of basic and clinical research for nearly 2 decades. Since the original descriptions of in vitro lymphocyte-mediated cytotoxicity against human tumor cells, there have been numerous attempts to exploit such observations for therapeutic use, with decidedly mixed results. Most studies have focused on the role of either natural killer cells or cytotoxic CD8 + alphabeta T cells as the primary mediators of antitumor cytotoxicity, and until recently little attention has been paid to the role of gammadelta T cells in this capacity. This is partially due to a lack of understanding of the mechanisms of gammadelta T-cell immune responses to tumors, as well as the practical problem of obtaining a sufficient number of gammadelta T cells for clinical-scale administration. In this article, we discuss the biological and clinical rationale for developing gammadelta T cell-based immunotherapies for the treatment of a variety of malignant conditions. It is our view that infusing supraphysiological numbers of tumor-reactive gammadelta T cells-either in the autologous or allogeneic setting-might be used to restore or augment innate immune responses against malignancies. Accordingly, we will also discuss how we and others are working to overcome some of the practical limitations that have so far limited the direct clinical delivery of highly purified human gammadelta T cells for the treatment of both hematologic and solid tumors.

Hematopoietic Stem Cell Transplantation↗

PubMed2005

Ex vivo expanded human Vgamma9Vdelta2+ gammadelta-T cells mediate innate antitumor activity against human prostate cancer cells in vitro.

PURPOSE: We have previously identified a CD2 mediated, interleukin-12 dependent signaling pathway that inhibits activation induced cell death in mitogen stimulated human gammadelta-T cells, permitting the large-scale expansion of these cells. Herein we report the innate antitumor activity of expanded human Vgamma9Vdelta2+ gammadelta-T cells against human prostate cancer cells. MATERIALS AND METHODS: Apoptosis resistant human gammadelta-T cells were expanded in vitro from cultured human peripheral blood mononuclear cells and then enriched to high purity by immunomagnetic separation. In vitro cytotoxicity of expanded gammadelta-T cells was measured against human prostate cancer cell lines using standard cytotoxicity assays. RESULTS: gammadelta-T cells derived from various donors consistently showed lytic activity against the prostate cancer cell lines DU-145 and PC-3 but not LNCaP. mAbs against Vgamma9 or Vdelta2 T-cell receptor chains as well as mAb against intercellular adhesion molecule-1 (ICAM-1) or CD18, the beta subunit of ICAM-1 counter receptors, blocked gammadelta-T cell mediated killing of prostate cancer cells. gammadelta-T cells lysed prostate cancer cell lines largely through the perforin/granzyme pathway. CONCLUSIONS: Ex vivo, expanded human Vgamma9Vdelta2+ gammadelta-T cells are able innately to recognize and kill certain human prostate tumor cell lines in vitro. The recognition and killing of prostate cancer cells occurs in a gammadelta-T-cell receptor dependent manner and it also appears to involve interactions between ICAM-1 and CD18. Because apoptosis resistant human Vgamma9Vdelta2+ gammadelta-T cells can readily be expanded to large numbers (clinical scale), these findings must be considered in the context of developing adoptive immunotherapy strategies to exploit gammadelta-T cell innate immune responses to prostate cancer.

Drug Screening Assays, Antitumor↗

PubMed2002

Human gammadelta-T cells in adoptive immunotherapy of malignant and infectious diseases.

Human gammadelta-T cells are capable of mediating both innate antitumor and antiviral activity, functions that theoretically might be exploitable in the treatment of a variety of malignant or infectious diseases. Nonetheless, experimental therapies incorporating the adoptive transter of human gammadelta-T cells have remained unfeasible to date owing largely to the difficulty of isolating or expanding sufficient numbers of gammadelta-T cells. It is in this context that recent discoveries from our laboratory are presented. By identifying specific signaling pathways that selectively inhibit activation-induced apoptosis in apoptosis-prone gammadelta-T cells, we have been able to expand large numbers of viable and functional human gammadelta-T cells, an undertaking until now notpossible. As important, these apoptosis-resistant gammadelta-Tcells appear to retain major histocompatibility complex-unrestricted (innate) antitumor activity against a wide variety of human tumor cells both in vitro and in vivo. Moreover, apoptosis-resistant gammadelta-T cells also display potent innate antiviral activity in vitro against human immunodeficiency virus-1. Both the biologic and practical implications of these findings are considered and discussed particularly as they relate to the development of future adoptive immunotherapy strategies.

Apoptosis↗

PubMed2001

Down-regulation of IL-2 receptor alpha (CD25) characterizes human gammadelta-T cells rendered resistant to apoptosis after CD2 engagement in the presence of IL-12.

We recently identified a CD2-mediated, IL-12-dependent signaling pathway that inhibits apoptosis in mitogen-stimulated human gammadelta-T cells. Here we show that gammadelta-T cells which acquire resistance to mitogen-induced apoptosis upregulate IL-12 receptor beta 1 subunit (IL-12Rbeta1); in contrast, gammadelta-T cells which remain sensitive to mitogen-induced apoptosis fail to express IL-12Rbeta1. Next we show that gammadelta-T cells which are rendered resistant to mitogen-induced apoptosis attenuate their expression of the IL-2 receptor alpha chain (IL-2Ralpha/CD25), this in part accounting for their acquired resistance to IL-2-induced death. In contrast, apoptosis-sensitive gammadelta-T cells are shown to persist in their expression of IL-2Ralpha/CD25, thus remaining sensitive to IL-2-induced death. Moreover, we show that apoptosis-resistant, but not apoptosis-sensitive, gammadelta-T cells display an enhanced responsiveness to IL-15, a finding in keeping with the known function of IL-15 as a growth and survival factor. Finally, we present evidence to suggest that this differential responsiveness to IL-15 occurs in part by the increased expression of the IL-15Ralpha chain on apoptosis-resistant gammadelta-T cells, compared to apoptosis-sensitive gammadelta-T cells. The biological and clinical implications of these findings are discussed.

Apoptosis↗