Abstract 1194: Adoptive cellular therapy overcomes tumor-induced dysregulation of myelopoiesis
Authors: Wildes Tyler J. , Flores Catherine T. , Dean Bayli DiVita , Grippin Adam , Dyson Kyle , Mitchell Duane A. 
Published: August 2019

INTRODUCTION: Hematopoietic stem and progenitor cell (HSPC) transfer during adoptive T cell immunotherapy (ACT) prolongs median survival and generates 30% long-term cures for malignant brain tumors. We recently demonstrated during ACT that intratumoral HSPCs differentiate into immune-activating dendritic cells (DCs) through T cell-released IFN-γ. We also determined that CCR2+ HSPCs are the key immune-activating progenitor population. We previously utilized syngeneic transfer of naive HSPCs that were not endemic to the recipient tumor-bearing host. This is different from the clinical paradigm of autologous transfers. This is important because in peripheral cancers tumor-bearing host (TB) HSPCs possess considerable immunosuppressive potential. It remains unknown if this is true in brain tumor-bearing hosts, and it remains unknown how this would impact HSPC+ACT immunotherapy. We therefore evaluated the immunologic function of naïve or TB HSPCs during immunotherapy.

METHODS: We utilized KR158B and GL261 intracranial gliomas to generate TB HSPCs. HSPC culture experiments were performed in RPMI alone or conditioned with T cell supernatants to study HSPC differentiation. In vivo treatment models utilized intracranial gliomas and intravenous transfer of HSPCs with ACT. Data from the immgen.org database was utilized for hypothesis generation.

RESULTS: Brain tumors promoted a 20% expansion of HSPCs including granulocyte monocyte precursors (GMP) but a loss of DC progenitors. The immgen database revealed that GMPs express high levels of IFN-γR1 while DC progenitors express high levels of IFN-γR2, CCR2, and CXCR4, the chemotactic receptor for HPSC homing. We next determined by flow cytometry that TB HSPCs express 40% more IFN-γR1 and 90% more IFN-γR2 on DC progenitors. To determine the differentiation preference of these cells, we performed in vitro culture. After a 3 day culture, naïve HSPCs differentiated into 30% myeloid-derived suppressor cells (MDSCs; CD11b+Ly-6G/6C+) while TB HSPCs differentiated into 60% MDSCs. When both cells types were cultured in activated tumor-specific T cell supernatants containing IFN-γ, both HSPC types differentiated into 30% MDSCs, 80% MHCII+ antigen-presenting cells, and 20% CD11c+MHCII+ DCs. In vivo, ACT rescued intratumoral TB HSPCs to prolong median survival and generate long-term cures. Additionally, TB HSPC-derived cells in brain tumors maintained higher IFN-γR2 and displayed non-inferior differentiation into DCs when compared naïve HSPCs. We are now investigating the impact of PD-1 blockade on TB HSPC function.

CONCLUSIONS: Gliomas exert an immunosuppressive pressure on HSPCs. However, ACT can overcome dysregulated TB HSPC programming and promote generation of DCs instead of MDSCs. A phase I trial evaluating the impact of HSPC transfer on adoptive immunotherapy in pediatric high-grade gliomas is underway at our center (ACTION; NCT03334305).

Citation Format: Tyler J. Wildes, Catherine T. Flores, Bayli DiVita Dean, Adam Grippin, Kyle Dyson, Duane A. Mitchell. Adoptive cellular therapy overcomes tumor-induced dysregulation of myelopoiesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1194.