Tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) are critically important determinants of solid tumor immunosuppression, neovascularization and metastatic dissemination. Despite intensive efforts aimed at identifying TAM/MDSC regulatory effectors, very few have been identified that can orchestrate this process and be effectively targeted. Macrophage migration inhibitory factor (MIF) is one the oldest cytokine activities described and is a centrally important mediator of monocyte/macrophage immune responses. TAMs and MDSCs from melanoma bearing MIF-deficient mice exhibit a unique reversion in their "polarization" state resulting in a switch from n immunosuppressive, angiogenic phenotype (MIF+/+ TAM/MDSC) into an immunostimulatory, non-angiogenic phenotype (MIF-/- TAM/MDSC) which results in significant reductions in primary and metastatic melanoma disease progression. Intriguingly, our previously discovered MIF small molecule antagonist - 4-iodo-6- phenylpyrimidine (4-IPP) - fully recapitulates MIF-deficiency, both in vitro and in vivo, and serves to attenuate TAM and MDSC alternative activation, immunosuppression, neoangiogenesis and melanoma disease progression . We very recently discovered that 4-IPP functionally inhibits MIF by dramatically reducing intracellular MIF protein levels in a proteasome-dependent manner. However, relatively high 4-IPP IC50 values and a lack of information on its mechanism of action, bioavailability and chronic toxicity dictate that much more study is needed to fully identify, optimize and characterize lead MIF-degradation inducing compounds before moving forward with small molecule MIF targeting in a clinical setting. To fulfill the stated objectives of this application, the following aims are proposed:
Aim 1 : Delineate the mechanisms of action of 4-IPP and MIF-dependent TAM/MDSC polarization, Aim 2: Characterize TAM/MDSC modulatory, in vivo bioavailability, toxicity and anti-tumor activities of existing and newly identified MIF inhibitor scaffolds, and Aim 3: Evaluate the therapeutic potential of lead MIF small molecule antagonists as individual and combinatorial modalities against established melanoma.
Malignant melanoma is the most deadly form of skin cancer due, in large part, to its aggressive ability to locally invade and distally metastasize. One in 50 Americans has a lifetime risk of developing melanoma, and nearly 69,000 people in the United States were diagnosed with it last year. The five year survival rate for those diagnosed with stage IV metastatic melanoma remains unacceptably low at only 5 - 10%. Despite the advent of new immunotherapies designed to enhance the patient's immune response to attack melanocytic cancer cells, no appreciable improvements have been observed in overall patient survival percentages. Our recent studies now demonstrate that small molecule targeting of macrophage migration inhibitory factor (MIF) induces substantial resistance to implantable subcutaneous and lung metastatic melanoma. Studies described in this proposal seek to fully delineate the mechanism(s) by which small molecule MIF antagonists induce intracellular degradation of MIF thereby reverting immunosuppressive, pro-angiogenic TAM/MDSC cell populations into immunostimulatory, non-angiogenic innate immune effector cells. These studies will rigorously characterize and refine the clinical efficacy of small molecule MIF targeting as both an individual and combinatorial therapeutic modality targeting malignant melanoma.
|Mitchell, Robert A; Yaddanapudi, Kavitha (2014) Stromal-dependent tumor promotion by MIF family members. Cell Signal 26:2969-78|