FasL gene knock-down therapy enhances the antiglioma immune response

Timothy Jansen, Betty Tyler, Joseph L. Mankowski, Violette Renard Recinos, Gustavo Pradilla, Federico Legnani, John Laterra, Alessandro Olivi

Research output: Contribution to journalArticlepeer-review

Abstract

Malignant glioma is a lethal form of brain cancer that is very difficult to treat. The aggressive behavior of these neoplasms and their limited responsiveness to therapy has been attributed in part to the ability of these tumors to evade the immune system. Gliomas, like many other solid tumors, express components of numerous immune escape mechanisms, including immunosuppressive proteins such as TGF-β, IL-10, and FasL. Here, we show that FasL expression can support the growth of experimental intracranial glioma. We show that FasL is readily detected in human glioblastoma multiforme clinical specimens. FasL was found to be expressed by three well-characterized rat glioma cell lines (9L, F98, and C6) and glioma cell-derived FasL mediated the death of phytohemagglutinin-stimulated Jurkat T-lymphocytes when cocultured with glioma cells in vitro. We asked if inhibiting 9L-derived FasL altered the growth of experimental glioma. FasL expression knockdown using shRNA reduced the growth of subcutaneous and intracranial 9L gliomas by ∼50% in immune competent Fisher 344 rats. In contrast, FasL expression knockdown had no affect on the growth of intracranial 9L glioma in T-cell deficient athymic rats. Intracranial tumors derived from FasL knockdown 9L glioma cells contained up to 3-fold more tumor infiltrating T-cells than tumors derived from control 9L cells. These results demonstrate that down-regulating FasL expression and/or function in glial malignancies can enhance T-cell tumor infiltration and inhibit tumor growth. The findings suggest that targeting endogenous FasL in glial malignancies could enhance the efficacy of emerging immune-based treatment strategies.

Original languageEnglish
Pages (from-to)482-489
Number of pages8
JournalNeuro-Oncology
Volume12
Issue number5
DOIs
Publication statusPublished - May 2010

Keywords

  • CD95L
  • Fas ligand
  • Glioma
  • Immunity
  • Immunotherapy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Clinical Neurology

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