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.