Abstract | BACKGROUND: Suboptimal activation of T lymphocytes by melanoma cells is often due to the defective expression of class I major histocompatibility antigens (MHC-I) and costimulatory molecules. We have previously shown that geranylgeranyl transferase inhibition (done with GGTI-298) stimulates anti- melanoma immune response through MHC-I and costimulatory molecule expression in the B16F10 murine model [1]. METHODOLOGY/PRINCIPAL FINDINGS: In this study, it is shown that vaccination with mIFN-gand GGTI-298 pretreated B16F10 cells induces a protection against untreated tumor growth and pulmonary metastases implantation. Furthermore, using a human melanoma model (LB1319-MEL), we demonstrated that in vitro treatment with hIFN-gamma and GGTI-298 led to the up regulation of MHC-I and a costimulatory molecule CD86 and down regulation of an inhibitory molecule PD-1L. Co-culture experiments with peripheral blood mononuclear cells (PBMC) revealed that modifications induced by hIFN-gamma and GGTI-298 on the selected melanoma cells, enables the stimulation of lymphocytes from HLA compatible healthy donors. Indeed, as compared with untreated melanoma cells, pretreatment with hIFN-gamma and GGTI-298 together rendered the melanoma cells more efficient at inducing the: i) activation of CD8 T lymphocytes (CD8+/CD69+); ii) proliferation of tumor-specific CD8 T cells ( MelanA-MART1/TCR+); iii) secretion of hIFN-gamma; and iv) anti- melanoma specific cytotoxic cells. CONCLUSIONS/SIGNIFICANCE: These data indicate that pharmacological treatment of melanoma cell lines with IFN-gamma and GGTI-298 stimulates their immunogenicity and could be a novel approach to produce tumor cells suitable for vaccination and for stimulation of anti- melanoma effector cells.
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Authors | Guillaume Sarrabayrouse, Christine Pich, Raphaël Moriez, Virginie Armand-Labit, Philippe Rochaix, Gilles Favre, Anne-Françoise Tilkin-Mariamé |
Journal | PloS one
(PLoS One)
Vol. 5
Issue 2
Pg. e9043
(Feb 03 2010)
ISSN: 1932-6203 [Electronic] United States |
PMID | 20140259
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- B7-2 Antigen
- Benzamides
- Cytokines
- GGTI 298
- Histocompatibility Antigens Class I
- Interferon-gamma
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Topics |
- Animals
- B7-2 Antigen
(immunology, metabolism)
- Benzamides
(pharmacology)
- Blotting, Western
- Cell Line, Tumor
- Coculture Techniques
- Cytokines
(metabolism)
- Cytotoxicity, Immunologic
(immunology)
- Female
- Flow Cytometry
- Histocompatibility Antigens Class I
(immunology, metabolism)
- Humans
- Interferon-gamma
(pharmacology)
- Jurkat Cells
- Leukocytes, Mononuclear
(cytology, immunology, metabolism)
- Melanoma
(immunology, metabolism, pathology)
- Melanoma, Experimental
(immunology, pathology)
- Mice
- Mice, Inbred C57BL
- T-Lymphocytes
(immunology, metabolism)
- Up-Regulation
(drug effects)
- Vaccination
(methods)
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