Glioblastoma (GBM) is the most common primary malignant brain tumor, with a median survival of up to 20 months. Males have a 1.6-fold higher incidence of GBM compared to females and worse disease outcome. Standard-of-care treatment and immunotherapies, which are currently in clinical trials, have had limited success improving patient outcome. An immunosuppressive microenvironment facilitating tumor progression and restricting anti-tumor immune response likely underlies therapeutic resistance. Although myeloid-derived suppressor cell (MDSCs) accumulate in patients with malignancies and play a critical role in the establishment of this immunosuppressive milieu, the mechanisms by which individual MDSC subsets promote tumorigenesis remain poorly defined. In pre-clinical models, I demonstrated that monocytic MDSCs (mMDSCs) infiltrated tumor at higher rates in males, while granulocytic MDSCs (gMDSCs) were more abundant in the peripheral circulation of females. Furthermore, there were more immunosuppressive myeloid cells in the tumors of male patients and gMDSC gene signature associated with poor prognosis of female patients. MDSC subset variation also determined sex-specific therapeutic response in preclinical models, including to fludarabine and anti-IL-1?. I also established that complement component 1q (C1q) is highly expressed by gMDSCs and elevated in females. Based on these observations, I hypothesize that MDSC subsets promote GBM progression via distinct mechanisms in a sex-specific manner and that their targeting will improve the efficacy of T cell-activating strategies.
Specific Aim 1 will test the hypothesis that mMDSCs and gMDSCs have distinct roles in local and systemic immunosuppression in a sex-specific manner.
This aim will investigate the changes in tumor growth, vascular density and immune activation status by adoptively transferring MDSC subsets and selectively depleting MDSCs in bone marrow chimeras.
Specific Aim 2 will test the hypothesis that the unique gene expression signatures of MDSC subsets makes them susceptible to distinct drugs that can be combined with checkpoint modulators. Sub-Aim 2A will examine the efficacy of drug candidates on MDSC activity in vitro and in vivo, while Sub-Aim 2B will attempt to achieve durable anti-tumor immune response by combining MDSC targeting strategies with anti-PD-1, anti-CTLA-4 and anti-OX40.
Specific Aim 3 will test the hypothesis that gMDSC- derived C1q promotes MDSC lineage commitment and systemic immunosuppression by evaluating tumor progression and checkpoint response in the absence of C1q. Sub-Aim 3A will use C1qa knockout bone marrow and C1q receptor inhibitors to determine MDSC fate.
Sub Aim 3 B will use pharmacological inhibitors combined with checkpoint modulators. These studies lay the foundation for my future research program and the development of novel immunotherapies for GBM by addressing variations in anti-tumor immunity, repurposing drugs and defining targetable pathways. These results are broadly applicable to other cancers and can lead to advanced treatment opportunities and improved patient outcome.
Suppression of anti-tumor immune response is a major mechanism facilitating the progression and therapeutic resistance of glioblastoma (GBM), the most malignant primary brain tumor. The objective of this project is to gain mechanistic insight into how differential accumulation and function of myeloid-derived suppressor cell (MDSC) subtypes in males versus females contribute to persistent GBM growth via suppression of local and systemic immunity, regulation of the complement system and re-programing the tumor microenvironment. The successful completion of this proposal will elucidate novel interventions targeting MDSC subset variation and account for sex as a biological variable for improved immunotherapy response, which will further be developed as part of my independent research program.
