Abstract A29: MIF controls human myeloid-derived immunosuppressive phenotype/function in melanoma educated CD14+ monocytes
Authors: Yaddanapudi Kavitha , Rendon Beatriz E. , Lamont Gwyneth J. , Eaton John W. , Mitchell Robert A. 
Published: May 2015

Abstract
Tumors suppress the host immune system by employing a variety of cellular immune modulators such as regulatory T cells, tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs). Recently, MDSCs have been recognized as critically important cellular immune modulators that serve to suppress both innate and adaptive immune responses in a wide variety of human malignancies. Macrophage migration inhibitory factor (MIF) is one the oldest cytokine activities described and is an important determinant of both innate and adaptive immune responses. Recent studies by our group revealed that MDSCs isolated from melanoma-bearing MIF-deficient mice are substantially less immunosuppressive than those isolated from MIF wildtype mice and these phenotypes correspond to significantly reduced primary and metastatic melanoma growth and progression. Importantly, 4-iodo-6-phenylpyrimidine (4-IPP – our previously discovered small MIF inhibitor) fully recapitulates MIF-deficiency in vitro and in vivo and serves to attenuate MDSC immunosuppression and melanoma disease progression in mice. To investigate whether MIF participates in human melanoma-induced MDSC differentiation and/or suppressive functions, an in vitro MDSC induction model was established using normal, primary human monocytes co-cultured with human melanoma cell lines in the presence or absence of the MIF antagonist, 4-IPP. Our studies suggest that the induction of CD14+/CD33+/HLADRlo/- myeloid-suppressive cells recently shown to represent the bulk of immunosuppressive activity in late stage melanoma patients is largely dependent on MIF. Importantly, small molecule inhibition of MIF in these MDSC-like cells almost completely abolishes their ability to suppress proliferation and IFN-gamma production by autologous T cells. Further, MIF-dependent suppressive activity of MDSCs is regulated via an NADPH oxidase induced ROS-mediated signaling mechanism. Finally, we demonstrate that small molecule inhibitors of MIF attenuate the suppressive properties of circulating CD14+/HLADRlo/- MDSCs isolated from stage III/IV melanoma patients confirming MIF as a critical mediator of MDSC-dependent immunosuppression in patients with advanced stage melanoma. These studies using human, clinically relevant experimental melanoma models lend strong support to the rationale that therapeutic inhibition of MIF in human melanoma MDSCs is a novel and clinically viable approach to enhancing anti-tumor T cell immunity in advanced melanoma patients.
Citation Format: Kavitha Yaddanapudi, Beatriz E. Rendon, Gwyneth J. Lamont, John W. Eaton, Robert A. Mitchell. MIF controls human myeloid-derived immunosuppressive phenotype/function in melanoma educated CD14+ monocytes. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A29. doi:10.1158/1538-7445.CHTME14-A29