Independent contributions of GR-1+ leukocytes and Fas/Fasl interactions to induce apoptosis following interleukin-12 gene therapy in a metastatic model of prostate cancer

Michael A. Sanford, Yan Ying, Steven E. Canfield, Waleed Hassan, William A. Selleck, Gertrude Atkinson, Shu Hsia Chen, Simon J. Hall

Research output: Contribution to journalArticle

Abstract

In a mouse model of prostate cancer, adenovirus-mediated interleukin-12 (Ad.mIL-12) gene therapy resulted in significant growth inhibition of both the injected primary tumor and synchronous metastases. Within 2 days of vector injection, two distinct patterns of apoptosis were detected within the primary tumor, the inhibition of which with a caspase inhibitor substantially negated growth suppression. The dominant pattern displayed localized sheets of apoptotic cells in close association with necrosis containing polymorphic neutrophils (PMNs). Depletion of PMNs resulted in the loss of this pattern of apoptosis and reduced growth suppression. A second major wave of growth suppression within the primary tumor was mediated by an immune response. Natural killer (NK) cell activity was detected within tumor-infiltrating lymphocytes (TIL) by the eighth day post-vector injection, the depletion of which resulted in a significant loss of survival enhancement. A more modest role for T cells was identified, which in the absence of documented cytotoxic T lymphocyte (CTL) activity may be related to a significant reduction in interferon-γ (IFN-γ) levels found in mice depleted of T cells, thereby reducing the secondary influences of IFN-γ. However, depletion of NK cells or T cells had no discernible negative effect on IL-12-mediated anti-metastatic activity. Attention focused on the role of IFN-γ, observed following Ad.mIL-12 therapy, to mediate the diffuse pattern of apoptosis seen in the primary and metastatic lesions. In vitro studies noted the ability of IFN-γ to up-regulate tumor cell expression of Fas and FasL to mediate apoptosis, whereasin vivo blockage of Fas/FasL interactions with soluble Fas resulted in a modest reduction in primary tumor growth suppression but complete abrogation within metastatic lesions.

Original languageEnglish (US)
Pages (from-to)1485-1498
Number of pages14
JournalHuman Gene Therapy
Volume12
Issue number12
DOIs
StatePublished - 2001
Externally publishedYes

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Interleukin-12
Genetic Therapy
Prostatic Neoplasms
Leukocytes
Interferons
Apoptosis
Growth
Neoplasms
T-Lymphocytes
Adenoviridae
Natural Killer Cells
Neutrophils
Tumor-Infiltrating Lymphocytes
Injections
Caspase Inhibitors
Cytotoxic T-Lymphocytes
Necrosis
Up-Regulation
Neoplasm Metastasis
Therapeutics

ASJC Scopus subject areas

  • Genetics

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Independent contributions of GR-1+ leukocytes and Fas/Fasl interactions to induce apoptosis following interleukin-12 gene therapy in a metastatic model of prostate cancer. / Sanford, Michael A.; Ying, Yan; Canfield, Steven E.; Hassan, Waleed; Selleck, William A.; Atkinson, Gertrude; Chen, Shu Hsia; Hall, Simon J.

In: Human Gene Therapy, Vol. 12, No. 12, 2001, p. 1485-1498.

Research output: Contribution to journalArticle

Sanford, Michael A. ; Ying, Yan ; Canfield, Steven E. ; Hassan, Waleed ; Selleck, William A. ; Atkinson, Gertrude ; Chen, Shu Hsia ; Hall, Simon J. / Independent contributions of GR-1+ leukocytes and Fas/Fasl interactions to induce apoptosis following interleukin-12 gene therapy in a metastatic model of prostate cancer. In: Human Gene Therapy. 2001 ; Vol. 12, No. 12. pp. 1485-1498.
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