Melanoma cells treated with GGTI and IFN-gamma allow murine vaccination and enhance cytotoxic response against human melanoma cells.

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.

• 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)

Chemical References

• B7-2 Antigen
• Benzamides
• Cytokines
• GGTI 298
• Histocompatibility Antigens Class I
• Interferon-gamma

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)