Melanoma Cells Treated with GGTI and IFN-[gamma] Allow Murine Vaccination and Enhance Cytotoxic Response against Human Melanoma Cells

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...

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Bibliographic Details
Published in:PloS one 2010-02, Vol.5 (2), p.e9043
Main Authors: Sarrabayrouse, Guillaume, Pich, Christine, Moriez, Raphaël, Armand-Labit, Virginie, Rochaix, Philippe, Favre, Gilles, Tilkin-Mariamé, Anne-Françoise
Format: Article
Language:English
Subjects:
Analysis
Cancer metastasis
Cancer prevention
HLA antigens
Melanoma
T cells
Vaccination
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Summary: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]. 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. 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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0009043