Abstract
Initially identified as a T lymphocyte-elicited inhibitor of macrophage motility, macrophage migration inhibitory factor (MIF) has since been found to be expressed by nearly every immune cell type examined and overexpressed in most solid and hematogenous malignant cancers. It is localized to both extracellular and intracellular compartments and physically interacts with more than a dozen different cell surface and intracellular proteins. Although classically associated with and characterized as a mediator of pro-inflammatory innate immune responses, more recent studies demonstrate that, in malignant disease settings, MIF contributes to anti-inflammatory, immune evasive, and immune tolerant phenotypes in both innate and adaptive immune cell types. This review will summarize the studies describing MIF in tumor-specific innate and adaptive immune responses and attempt to reconcile these various pleiotropic functions in normal physiology.
Highlights
Tumor immune responses are shaped and characterized by a number of factors [1] including mutational burden, inflammatory response, differential expression of cytokines and chemokines, and the presence and/or activation of both tumoral and stromal immune suppressive checkpoint ligands and receptors.Originally identified over 50 years ago as a secreted lymphocyte product associated with macrophage-dependent delayed-type hypersensitivity [2, 3], migration inhibitory factor (MIF) has become one of the most enigmatic regulators of innate and adaptive immune responses
Studies that looked at dendritic cell (DC) MHC-II expression found that MIF promotes downregulation of MHC-II [104, 112], which further suggests that MIF may impair tumor antigen presentation of DCs to CD4+ T cells. These findings suggest that MIF promotes tumor-associated immune evasion by inhibiting DC infiltration, maturation, and antigen presentation; all of which are inherently required for the development of anti-tumor CD4+ and CD8+ T cell effector functions
In another study investigating a non-melanoma skin cancer (NMSC) mouse model induced by chronic UVB exposure [123], MIF-deficient mice exhibited reduced tumor growth that corresponded to significant reductions in dermal neutrophil infiltration and associated myeloperoxidase activity
Summary
Tumor immune responses are shaped and characterized by a number of factors [1] including mutational burden, inflammatory response, differential expression of cytokines and chemokines, and the presence and/or activation of both tumoral and stromal immune suppressive checkpoint ligands and receptors. In another study (please see Table 1 for a summary of noted studies used for this review and corresponding references) investigating a non-melanoma skin cancer (NMSC) mouse model induced by chronic UVB exposure [123], MIF-deficient mice exhibited reduced tumor growth that corresponded to significant reductions in dermal neutrophil infiltration and associated myeloperoxidase activity This finding is interesting as NMSC tumor initiation is largely due to enduring inflammatory responses and highlights the fact that MIF’s effect as a pro-inflammatory cytokine can promote tumor growth in the context of chronic inflammation. Using a murine model of psoriasiform dermatitis induced by IL-23—a critical determinant of Th17 lymphocyte responses [178]—MIFdeficiency resulted in a dramatic reduction of disease progression [179]
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