Cancer Immune Therapy Edited by G. Stuhler and P. Walden ...

130 7 Immunosuppresive Factors in Cancer
7.3
Macrophage Migration Inhibitory Factor (MIF)
MIF was originally described in the 1960s as a product of activated T cells that inhibited
the random migration of guinea pig macrophages [175, 176]. Later studies revealed
the critical role of MIF in the host inflammatory response to endotoxin [177,
178]. Over the past decade, a large body of work described a role for MIF in the regulation
of host inflammatory responses (reviewed in [179, 180]). Inhibition of MIF
using neutralizing antibodies significantly reduces the severity of inflammatory diseases
including arthritis [181±183], peritonitis [184] and glomerulonephritis [185]. In
addition to its pro-inflammatory activity, our laboratory and others have identified
the role of MIF as an immunomodulatory factor in T cell activation and antigen-specific
T cell responses in vitro and in vivo [186, 187].
It is now known that numerous cell types found in most organs constitutively express
MIF, including immune cells (reviewed in [179, 180]). However, the expression
of MIF is significantly higher in tumor cells than normal cells [188±192]. Furthermore,
enhanced tumor MIF expression positively correlates with a more invasive
phenotype [189]. More recent studies suggest a role for MIF in positively regulating
cellular proliferation [193±197].
The identification of the potential growth-promoting function of MIF led us to examine
the effect of MIF neutralization on tumor growth in vivo. We found that MIF
blockade significantly inhibited tumor growth and tumor-associated angiogenesis
[198]. Similar observations demonstrating the growth promoting and pro-angiogenic
functions of MIF were reported by other groups using experimental models of melanoma
[199] and colon adenocarcinoma [200]. However, no direct effect of MIF on tumor
cell proliferation has been reported.
Recent studies demonstrate the role of MIF in inhibiting NK-mediated lysis of endothelial
cells [201] and uveal melanoma cells [202]. These studies suggest that tumor
cells may secrete high levels of MIF to protect themselves from host NKmediated
destruction. More recently, our laboratory examined the effect of MIF neutralization
on CTL responses during tumor growth. Using the ovalbumin-specific
EG7 tumor cell model, we found that MIF immunoneutralization delays tumor
growth, and was associated with increased CTL activity, an accumulation of intra-tumoral
CD8 + T cells, enhanced tumor-associated apoptosis and increased CD8 + T cell
migration to the tumor [203]. These observations are important because cellmediated
tumor destruction relies on a rapid, extensive and sustained infiltration of
killer T cells [204±207]. Thus, we hypothesize that tumor-derived MIF promotes host
immune suppression and prevents tumor destruction. More interestingly, these observations
also raise the possibility that additional unidentified immunosuppressive
factors might exist.