Tumor-driven myeloid-derived suppressor cell (MDSC) expansion in the marginal zone (MZ) of the spleen is critical for suppression of anti-tumor CD8+ T cell responses in vivo. In previously published data we reported that marginal zone-resident macrophages (MZ MFs) are critical sensors for cellular debris in circulation driving early tolerogenic responses and preventing auto-immunity. When we examined the spleens of tumor- bearing mice we found significant expansion of MDSCs in the MZ in contact with MZ MFs. Deletion of MZ MFs abrogated tumor-induced splenic IL-6 and CCL2 expression and MDSC expansion suggesting a previously unknown mechanistic relationship between MZ MFs and MDSCs. Moreover, we found MDSC activation induced differentiation and suppression required engagement of the GCN2 arm of the integrated stress response which, in turn, drove expression of the myeloid differentiation factor C/EBP. In this proposal we hypothesize MZ MF-dependent expansion of MDSCs and GCN2-driven acquisition of suppressive function are related with MZ MFs providing the early signals driving MDSC recruitment to the MZ and activation. Our project will examine how tumors impact MZ MF expression of pro-MDSC factors and determine the functional relationship between this and GCN2 signal activation in MDSC precursors. If successful, the findings from this project would provide new insight into the contribution of microenvironment and stromal macrophages in tumor-mediated suppressive processes as well as provide novel therapeutic targets for cancer immuno-therapy.
Natural suppression of immune responses against cancer-cell proteins is a significant barrier to targeted immuno-therapy. Recently we found tumors induce expansion of a population of immune suppressive cells in the spleen in contact with a population of scavenging cells, which we had previously reported are critical for inducing immune suppression to cell debris. In our preliminary research we have found that these scavenging cells (macrophages) are required for tumor-driven expansion of the immune suppressive cells (MDSCs). Surprisingly, we also found a stress response generally associated with protein starvation is activated in MDSCs and is required for their development and suppressive characteristics. Herein we predict the two observations are related and cancer-mediated immune suppression requires the action of macrophages and activation of the protein starvation response in MDSCs leading ultimately to suppression of anti-tumor inflammatory immunity. In this proposal we will seek to define the role for macrophages and starvation stress signals in cancer-induced immune suppression and test the theory that blocking this pathway will provide therapeutic benefit in animal models of lymphoma and melanoma.
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