within intracranial tumors generated using GBM cell lines and neurospheres derived from ... from the TME of GL26 intracranial tumor bearing mice inhibited.
Neuro-Oncology 17:v221 –v225, 2015. doi:10.1093/neuonc/nov236.14
TMIC-14. DEPLETION OF GLIOMA INFILTRATING MYELOID DERIVED SUPPRESSOR CELLS PROMOTES ANTI-TUMOR T CELL RESPONSES Neha Kamran, Youping Li, Mariela Moreno Ayala, Nicholas Raja, Felipe Nunez, Hikmat Assi, Pedro Lowenstein, and Maria Castro; University of Michigan, Ann Arbor, MI, USA MDSCs represent a population of immature myeloid cells at various stages of differentiation that have the potential to inhibit anti-tumor T cell immunity. We demonstrate the accumulation of MDSCs in the tumor microenvironment (TME) of glioma (GBM) bearing mice. A massive influx of MDSCs was noted within intracranial tumors generated using GBM cell lines and neurospheres derived from tumors. Interestingly both the percentage and absolute number
of MDSCs was significantly enhanced in the blood of moribund mice. Expansion of MDSCs was not observed in the bone marrow or spleens of GBM bearing animals. While both Gr-1high and Gr-1low MDSCs isolated from the TME of GL26 intracranial tumor bearing mice inhibited antigen-specific T cell proliferation, Gr-1low MDSC were observed to be more efficient. Gr-1high or Gr-1low MDSCs from the bone marrow of intracranial tumor bearing mice failed to suppress antigen-specific T cell proliferation suggesting that TME derived factors may activate MDSCs to exert their immune-suppressive properties. Additionally MDSCs within the TME were phenotypically distinct from the MDSCs from the spleens of tumor bearing animals as indicated by the expression of IL-4Ra, PD-L1 and cytokine release. In vivo, depletion of MDSCs significantly enhanced the median survival of GBM bearing mice. Furthermore, when combined with Ad-TK + Ad-FLT3L immune stimulatory-gene therapy, MDSC depletion significantly enhanced the frequency of tumor-specific T cells within the TME and increased IFN-g production by splenic T cells. A trend for increased IFN-g+ CD8 T cells within the glioma TME was also observed. Overall, our data suggests that strategies that inhibit MDSC recruitment to the GBM TME and/or block their activity could enhance the T cell mediated tumor clearance and provide survival benefit.
Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2015.