Many
tumors down-regulate major histocompatibility complex (MHC)
antigen expression to evade host immune surveillance. However, there are very few in vivo models to study MHC
antigen expression during
tumor spontaneous regression. In addition, the roles of
transforming growth factor betal (TGF-beta1),
interferon gamma (IFN-gamma), and
interleukin (IL)-6 in modulating MHC
antigen expression are ill understood. We previously reported that tumor infiltrating lymphocyte (TIL)-derived
IL-6 inhibits
TGF-beta1 and restores natural killing (NK) activity. Using an in vivo canine-
transmissible venereal tumor (CTVT)
tumor model, we presently assessed
IL-6 and
TGF-beta involvement associated with the MHC
antigen expression that is commonly suppressed in
cancers.
IL-6, IFN-gamma, and
TGF-beta1, closely interacted with each other and modulated MHC
antigen expression. In the presence of
tumor-derived
TGF-beta1, host IFN-gamma from TIL was not active and, therefore, there was low expression of MHC
antigen during
tumor progression. TGF-beta1-neutralizing antibody restored IFN-gamma-activated MHC
antigen expression on
tumor cells. The addition of exogenous
IL-6 that has potent anti-TGF-beta1 activity restored IFN-gamma activity and promoted MHC
antigen expression. IFN-gamma and
IL-6 in combination acted synergistically to enhance the expression of MHC
antigen. Thus, the three
cytokines,
IL-6,
TGF-beta1, and IFN-gamma, closely interacted to modulate the MHC
antigen expression. Furthermore,
transcription factors, including STAT-1, STAT-3, IRF-1,
NF-kappaB, and CREB, were significantly elevated after
IL-6 and IFN-gamma treatment. We conclude that the host
IL-6 derived from TIL works in combination with host IFN-gamma to enhance MHC molecule expression formerly inhibited by
TGF-beta1, driving the
tumor toward regression. It is suggested that the treatment of
cancer cells that constitutively secrete
TGF-beta1 should incorporate anti-
TGF-beta activity. The findings in this in vivo
tumor regression model have potential applications in
cancer immunotherapy.