Geranylgeranyl transferase inhibition stimulates anti-melanoma immune response through MHC Class I and costimulatory molecule expression.
Defective antitumor immune responses are frequent consequences of defects in the expression of major histocompatibility complex (MHC) class I and costimulatory molecules. We demonstrated that statins, inhibitors of HMGCoA reductase, enhance mIFN-gamma induced expression of MHC class I antigens on murine B16F10 melanoma. GGTI-298, a geranylgeranyl transferase I inhibitor, but not FTI-277, a farnesyl transferase inhibitor, mimics this effect of statins. This effect is related to peptide transporter protein TAP1 up-regulation. Simultaneously, GGTI-298 induces the expression of CD80 and CD86 costimulatory molecules. C3 exoenzyme, which selectively inactivates Rho proteins, phenocopies the effects of GGTI-298, indicating a role for Rho proteins in these events. Furthermore, the treatment of B16F10 cells with GGTI-298 or C3 exoenzyme associated with mIFN-gamma induces in vivo tumor growth slowing down in immunocompetent but not in nu/nu syngeneic mice. Both in vivo injections and in vitro restimulation of splenocytes with GGTI-298- and mIFN-gamma-treated B16F10 cells induces an enhancement of specific CD8 T lymphocytes labeled by TRP-2/H-2K(b) tetramers. Finally, these effects are not limited to mouse models since they were also reproduced in two human melanoma cell lines. These observations indicate that protein geranylgeranylation as well as Rho protein are critical for costimulatory and IFN-gamma-dependent MHC class I molecule expression in melanoma.
INSERM U563 CPTP, Département Innovation thérapeutique et Oncologie Moléculaire, Toulouse, France. tilkin@icr.fnclcc.fr
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AF
Tilkin-Mariamé
C
C
Cormary
N
N
Ferro
G
G
Sarrabayrouse
I
I
Lajoie-Mazenc
J-C
JC
Faye
G
G
Favre
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D018122:B7-1 Antigen / Q000032:analysis / Q000502:physiology*; D051940:B7-2 Antigen / Q000032:analysis / Q000502:physiology*; D001549:Benzamides / Q000494:pharmacology*; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006183:H-2 Antigens / Q000502:physiology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL
D018122:B7-1 Antigen; D051940:B7-2 Antigen; D001549:Benzamides; D004791:Enzyme Inhibitors; C102521:GGTI 298; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007371:Interferon-gamma; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I