The role of adoptive cellular therapy on myeloid-derived suppressor cell depletion in glioma

University Of Florida, Gainesville FL

Investigators

Abstract

Project Summary/Abstract Malignant brain tumors are the leading cause of cancer-related death in children and a significant cause morbidity and mortality in adults. Despite aggressive treatment, outcomes remain dismal and limited by a highly immunosuppressive tumor microenvironment which includes myeloid-derived suppressor cells (MDSCs). A promising therapeutic alternative developed by our group is called adoptive cellular therapy (ACT) which includes myeloablative host conditioning accomplished using total body irradiation (TBI), hematopoietic stem cell rescue, tumor-specific T cell transfer, and dendritic cell vaccine. ACT demonstrated significant improvements in overall survival across multiple brain cancer models, leading to pivotal approvals by the FDA for several investigational new drug applications. Our group has observed that ACT dramatically alters the glioma microenvironment. Hematopoietic stem cells migrate to the glioma microenvironment and differentiate to dendritic cells, which displace host-derived myeloid-derived suppressor cells. Additionally, hematopoietic stem cells secrete CCL3, promoting T cell infiltration into the glioma microenvironment. These observations suggest that the glioma microenvironment is radically altered after ACT and that other mechanisms may influence the cellular milieu underlying ACT’s efficacy. It is the goal of this proposal to elucidate the impact of ACT as it related to overcoming glioma immunosuppression and specifically the MDSC niche. Our preliminary data support our notions that ACT dramatically impacts the MDSC niche in glioma: (1) ACT mediated intratumoral depletion of MDSCs and reduced their proliferative capacity, (2) ACT promoted accumulation of MDSCs in secondary lymphoid organs, (3) repopulation of the glioma microenvironment with MSDCs was abrogated by ACT, (4) myeloproliferative chemokines were significantly reduced in the glioma microenvironment following ACT. Given these premises, two aims have been proposed to study this novel relationship in glioma. Aim 1 will identify the mechanisms governing MDSC depletion in ACT. To achieve this, flow cytometry-based assays will quantify cell apoptosis and cell death in addition to innovative use of gold nanorods and computed tomography to translationally measure cell migration in vivo. This aim is supplemented by multiplex analysis of cytokines and chemokines found in the glioma microenvironment to sustain future efforts in identifying the specific soluble molecules governing MDSC migration. Aim 2 will assess the impact of brain irradiation on MDSC accumulation and ACT efficacy. Following a survival study, we will leverage geo-spatial genomics approaches in conjunction with our gold nanorod imaging modality to track cells. This work is significant because depletion of immunosuppressive MDSCs represents a significant barrier to efficacious immunotherapy development. This project is innovative because it will utilize gold nanorods (GNRs) to elucidate in vivo migration of MDSCs in ACT-treated mice. These translational findings will optimize host conditioning protocols to maximize antitumor immune responses, limit iatrogenic toxicity, and reveal cellular mechanisms of overcoming cancer-driven immunosuppression.