Targeted STAT3 inhibition impairs MDSC mobilization and recruitment in glioblastoma

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Project Summary/Abstract Glioblastoma (GBM) is a universally lethal tumor for which standard of care has not changed in over 10 years. Unfortunately, immunotherapies that produce durable responses in other aggressive cancers have failed against GBM. One major obstacle limiting their efficacy is the opposing immunosuppressive actions levied by myeloid- derived suppressor cells within the tumor microenvironment. STAT3 expression is enriched in GBM, and is a negative prognostic indicator of survival. Moreover, active STAT3 (phosphorylated at tyrosine 705, P-STAT3) is a specific marker of MDSC cells, and plays an important role in their phenotypic polarization. While the existing evidence strongly justifies the role of STAT3 as a driver of tumorigenesis and practical target for anti-cancer therapy, the functional role of STAT3 in distal MDSC immune cells remains unresolved. In this proposal I provide preliminary evidence that supports that STAT3 is activated in polymorphonuclear MDSC (PMN-MDSC) cells within the bone marrow of tumor bearing syngeneic mice, and that pharmacologic inhibition with the small molecule drug LLL12B greatly reduces the number of PMN-MDSCs that enter systemic circulation. These findings highlight a critically important role for STAT3 in the mobilization of PMN-MDSCs in response to tumor presence, as well as a novel mechanism of anti-tumor action for LLL12B and other specific inhibitors of STAT3. Implementing a number of advanced techniques including high resolution microscopy, flow cytometry, and single cell RNA sequencing, I outline experiments utilizing syngeneic models of GBM designed to 1) characterize which immune cells within GBM express P-STAT3, 2) determine whether this activation occurs locally within the tumor or peripherally, and 3) identify the mechanistic role of STAT3 in governing PMN-MDSC trafficking. I hypothesize that targeted inhibition of STAT3 will block PMN-MDSC mobilization from the bone marrow, preventing them from accumulating within GBM tumors. This ultimately will shift the immunogenic balance from immune- suppressive to pro-inflammatory, allowing for immune mediated detection and killing of cancer cells.