title: FasL gene knock-down therapy enhances the antiglioma immune response.
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-beta, 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 approximately 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.
authors.affiliation: Departments of Neurosurgery, Fondazione IRCCS Istituto Nazionale C Besta, Milan, Italy.
authors.forename: Timothy
authors.initials: T
authors.lastname: Jansen
authors.forename: Betty
authors.initials: B
authors.lastname: Tyler
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Mankowski
authors.forename: Violette Renard
authors.initials: VR
authors.lastname: Recinos
authors.forename: Gustavo
authors.initials: G
authors.lastname: Pradilla
authors.forename: Federico
authors.initials: F
authors.lastname: Legnani
authors.forename: John
authors.initials: J
authors.lastname: Laterra
authors.forename: Alessandro
authors.initials: A
authors.lastname: Olivi
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics* / Q000276:immunology* / Q000628:therapy; D053222:Fas Ligand Protein / Q000235:genetics* / Q000276:immunology; D055785:Gene Knockdown Techniques; D015316:Genetic Therapy / Q000379:methods*; D005910:Glioma / Q000235:genetics* / Q000276:immunology* / Q000628:therapy; D006801:Humans; D015151:Immunoblotting; D051381:Rats; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019139:Tumor Escape / Q000235:genetics / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D053222:Fas Ligand Protein
references.citation: Br J Cancer. 2007 Sep 3;97(5):637-45
references.pmid: 17667919
references.citation: Cancer Res. 1993 Jan 15;53(2):329-33
references.pmid: 8417826
references.citation: Cytokine Growth Factor Rev. 2008 Feb;19(1):65-77
references.pmid: 18061513
references.citation: Int J Oncol. 2007 Jan;30(1):273-81
references.pmid: 17143538
references.citation: Br J Cancer. 2001 Sep 28;85(7):1047-54
references.pmid: 11592778
references.citation: Ann Oncol. 2005;16 Suppl 1:i64-5
references.pmid: 15888760
references.citation: Carcinogenesis. 2007 May;28(5):1067-73
references.pmid: 17183065
references.citation: Cancer Res. 2009 Feb 1;69(3):855-62
references.pmid: 19141642
references.citation: Mol Cancer Res. 2008 Jan;6(1):139-50
references.pmid: 18234969
references.citation: Cancer Res. 2006 Jun 1;66(11):5527-36
references.pmid: 16740684
references.citation: J Neurosurg. 2002 Mar;96(3):580-4
references.pmid: 11883844
references.citation: J Neuroimmunol. 2002 Aug;129(1-2):10-7
references.pmid: 12161015
references.citation: Brain Res. 1996 Aug 26;731(1-2):161-70
references.pmid: 8883866
references.citation: J Immunol. 2003 Oct 15;171(8):3947-54
references.pmid: 14530312
references.citation: Electrophoresis. 2001 Jun;22(10):1887-93
references.pmid: 11465484
references.citation: Science. 1995 Nov 17;270(5239):1189-92
references.pmid: 7502042
references.citation: Brain Pathol. 1997 Jul;7(3):863-9
references.pmid: 9217971
references.citation: Chem Immunol Allergy. 2007;92:140-154
references.pmid: 17264490
references.citation: Am J Pathol. 2006 Oct;169(4):1415-26
references.pmid: 17003496
references.citation: Exp Cell Res. 1998 Oct 10;244(1):302-9
references.pmid: 9770373
references.citation: Annu Rev Genomics Hum Genet. 2002;3:101-28
references.pmid: 12142355
references.citation: Cytokine Growth Factor Rev. 1996 Jun;7(1):93-102
references.pmid: 8864357
references.citation: J Clin Invest. 1997 Mar 15;99(6):1173-8
references.pmid: 9077524
references.citation: Cancer Res. 1998 Jan 15;58(2):302-9
references.pmid: 9443409
references.citation: Oncogene. 2009 Feb 5;28(5):721-33
references.pmid: 19029949
references.citation: Crit Rev Oncog. 1993;4(5):493-540
references.pmid: 8241322
references.citation: Cancer Immunol Immunother. 2007 Jan;56(1):48-59
references.pmid: 16612596
references.citation: Cancer Immunol Immunother. 2009 Feb;58(2):259-70
references.pmid: 18594817
references.citation: Hepatol Res. 2003 Dec;27(4):309-314
references.pmid: 14662119
references.citation: Cancer Res. 2005 Jun 15;65(12):5248-55
references.pmid: 15958570