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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.
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Submitted on : Monday, February 15, 2010 - 2:30:15 PM
Last modification on : Tuesday, June 30, 2020 - 3:10:55 AM
Long-term archiving on: : Friday, June 18, 2010 - 8:42:03 PM

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Guillaume Sarrabayrouse, Christine Pich, Raphaël Moriez, Virginie Armand-Labit, Philippe Rochaix, et al.. Melanoma Cells Treated with GGTI and IFN-gamma Allow Murine Vaccination and Enhance Cytotoxic Response against Human Melanoma Cells.. PLoS ONE, Public Library of Science, 2010, 5 (2), pp.e9043. ⟨10.1371/journal.pone.0009043⟩. ⟨inserm-00456571⟩

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