Glioblastoma (GBM) is the most prevalent primary malignant brain tumor and has a median survival of only 12- 15 months with the standard-of-care therapies including surgery, radiation, and chemotherapy. Under physiological conditions, the immune system is intended to remove irregular cancerous cells; however, tumors have evolved mechanisms to halt the immune response. Our laboratory previously identified myeloid-derived suppressor cells (MDSCs) as an immune suppressive cell population in GBM peripheral blood and the tumor microenvironment that correlates with decreased survival and immune response. Macrophage migration inhibitory factor (MIF) was determined to be a GBM-derived factor that promoted MDSC activation. I hypothesize that MIF induces and activates MDSCs through activation of the CD74 and CXCR2 receptors, driving the immune suppressive phenotype in GBM.
Aim 1 will test the hypothesis that MIF signaling is critical for the induction and activation of MDSCs by the use of an in vitro co-culture system I have adapted for the study of GBM-derived MDSCs. This system allows for the rapid production of MDSCs in biological replicates to study the role of MIF and its receptors in enhancing MDSC proliferation and MDSC function.
Aim 2 will test the hypothesis that MIF receptors are essential for GBM immune suppression in vivo by analyzing survival along with immune cell infiltration in the GBM microenvironment. These results will identify whether these receptors are a target for future immune therapies aimed at reducing the MDSC population to enhance the immune response. Based on previous studies that identified the MIF signaling axis as a moderator of MDSC activation within the GBM microenvironment and with the in vitro co-culture system and a MIF-secreting mouse model of glioma, I am in an optimal position to investigate the MIF signaling axis and how it affects MDSC induction, activation, and immune suppression.
Glioblastoma is the most prevalent primary malignant brain tumor and remains uniformly fatal despite aggressive therapies including surgery, radiation, and chemotherapy. In glioblastoma, there is a population of survival-predictive, immune-suppressive cells called myeloid-derived suppressor cells that are stimulated by tumor-derived macrophage migration inhibitory factor (MIF). The identification of this relationship has driven new inquiries about how MIF alters MDSC biology through the MIF receptors (CXCR2 and CD74) in GBM and is the basis of my fellowship application.
| Alban, Tyler J; Alvarado, Alvaro G; Sorensen, Mia D et al. (2018) Global immune fingerprinting in glioblastoma patient peripheral blood reveals immune-suppression signatures associated with prognosis. JCI Insight 3: |
