Macrophage migration inhibitory factor regulates triple-negative breast cancer progression by enhancing the recruitment of immune suppressive cells

Abstract Triple-negative breast cancer (TNBC) accounts for 15-20% of all breast cancers and lacks the expression of estrogen, progesterone, and Her2 receptors. TNBC is a highly aggressive subtype of breast cancer that has been associated with poorer prognosis and worse overall survival rate. Macrophage migration inhibitory factor (MIF) is a multipotent pro-inflammatory cytokine, highly expressed in various cancers and reported to enhance tumor growth and metastasis. However, its role in influencing the anti-tumor immunity is unexplored. We have previously shown that MIF promotes TNBC growth and metastasis. In addition, CPSI-1306 (MIF inhibitor), reduces its oncogenic effects. Here, we have shown that MIF downregulation in human TNBC xenografts correlate with reduced infiltration of myeloid derived suppressor cells (MDSCs). Furthermore, using a MIF knockout mouse model, we detected reduced MDSC population in the tumor microenvironment. In addition, we observed higher recruitment and increased proliferation of CD3+ T cells. Furthermore, we utilized a syngeneic mouse model to study the effect of MIF inhibition on infiltration of different immune cells in-vivo. CPSI-1306 treatment decreased the recruitment of MDSCs in both the tumor and spleen. In addition, CPSI-1306 treatment promotes the infiltration of CD8+ T cells in both the tumor and spleen. However, CPSI-1306 treatment did not influence the recruitment of CD4+ T cells. We further analyzed the expression of various cytokines and chemokines in blood sera of control and CPSI-1306 treated mice groups using a cytokine array kit. We observed that CPSI-1306 treatment group showed reduced levels of GCSF, GMCSF, IL-2 and IL-4 levels compared to vehicle control groups. Overall, our data strongly suggests that small molecular weight MIF inhibitors could be a potential strategy against TNBC. Citation Format: Manish Charan, Subhadip Das, Sanjay Mishra, Sanjay Varikuti, Abhay R Satoskar, Ramesh K Ganju. Macrophage migration inhibitory factor regulates triple-negative breast cancer progression by enhancing the recruitment of immune suppressive cells [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-04-12.