Exploiting the Innate Antitumor Activity of Human Gamma-Delta T-Cells for the Treatment of Prostate Cancer

Abstract

We initially identified and characterized a CD2-mediated, interleukin (IL)-12-dependent signaling pathway which inhibits apoptosis in mitogen-stimulated human gamma delta-T cells. We have since exploited this pathway to develop the methodologies allowing the large-scale ex vivo expansion of viable apoptosis-resistant gamma delta-T cells. We have shown that apoptosis-resistant human gamma delta-T cells retain significant innate, major histocompatibility complex (MMC)-unrestricted cytotoxicity against human prostate cancer cell lines. Purpose and scope: The aims of this project are, 1) to more precisely characterize the extent and breadth of the antitumor cytotoxicity mediated by apoptosis-resistant human gamma delta-T cells against human prostate cancer cells; 2) to define the general mechanisms involved in the recognition and lysis of sensitive prostate cancer cells by apoptosis-resistant 7&T cells; and 3) to determine the extent to which apoptosis-resistant gamma delta-T cells can regulate the growth and metastasis of prostate cancer cells in vivo. Key fin dings to date: 1) gamma delta-T cells derived from a variety of donors consistently displayed lytic activity against prostate cancer cell lines DU-145 and PC-3, but not LNCaP. 2) Monoclonal antibodies (mAb) against either the V gamma 9 or V delta TCR chains as well as mAb against intercellular adhesion molecules-1 (ICAM-1) or CD18 (beta subunit of the beta 2 integrins) blocked gamma delta-T cell-mediated killing of prostate cancer cells; 3) gamma delta-T cells lyse prostate cancer cell lines largely through the perform/granzyme pathway. 4) Using the TRAMP transgenic mouse model of prostate cancer, we have shown that the absence of gamma delta-T cells is indeed permissive for the development of tumors.

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Document Details

Document Type
Technical Report
Publication Date
Apr 01, 2004
Accession Number
ADA427821

Entities

People

  • Richard D. Lopez

Organizations

  • University of Alabama

Tags

DTIC Thesaurus Topics

  • Adaptive Immunity
  • Apoptosis
  • Biomedical Research
  • Blood
  • Cancer
  • Cell Line
  • Cell Physiological Processes
  • Cells
  • Immune System
  • Lymphocytes
  • Molecules
  • Neoplasms
  • Prostate Cancer
  • Standards
  • T Lymphocytes
  • Therapy
  • Tumor Cell Line

Fields of Study

  • Biology
  • Medicine

Readers

  • Oncology (Cancer Research).