CCR2 inhibition reduces tumor myeloid cells and unmasks a checkpoint inhibitor effect to slow progression of resistant murine gliomas

Top Cited Papers
Publisher Website
Google Scholar
Abstract
Immunotherapy directed at the PD-L1/PD-1 axis has produced treatment advances in various human cancers. Unfortunately, progress has not extended to glioblastoma (GBM), with phase III clinical trials assessing anti-PD-1 monotherapy failing to show efficacy in newly diagnosed and recurrent tumors. Myeloid-derived suppressor cells (MDSCs), a subset of immunosuppressive myeloid derived cells, are known to infiltrate the tumor microenvironment of GBM. Growing evidence suggests the CCL2–CCR2 axis is important for this process. This study evaluated the combination of PD-1 blockade and CCR2 inhibition in anti-PD-1–resistant gliomas. CCR2 deficiency unmasked an anti-PD-1 survival benefit in KR158 glioma-bearing mice. CD11b+/Ly6Chi/PD-L1+ MDSCs within established gliomas decreased with a concomitant increase in overall CCR2+ cells and MDSCs within bone marrow of CCR2-deficient mice. The CCR2 antagonist CCX872 increased median survival as a monotherapy in KR158 glioma-bearing animals and further increased median and overall survival when combined with anti-PD-1. Additionally, combination of CCX872 and anti-PD-1 prolonged median survival time in 005 GSC GBM-bearing mice. In both models, CCX872 decreased tumor associated MDSCs and increased these cells within the bone marrow. Examination of tumor-infiltrating lymphocytes revealed an elevated population, increased IFNγ expression, indicating enhanced cytolytic activity, as well as decreased expression of exhaustion markers in CD4+ and CD8+ T cells following combination treatment. These data establish that combining CCR2 and PD-1 blockade extends survival in clinically relevant murine glioma models and provides the basis on which to advance this combinatorial treatment toward early-phase human trials. Significance Standard of care for glioblastoma (GBM) results in median survival of <15 mo with 5-y survival <10%, highlighting the need for novel treatments. Immune checkpoint blockade has been successful in various cancer subtypes. However, success has not extended to GBM, largely due to the characteristically immune-suppressive glioma microenvironment. Here, we report targeting of myeloid derived suppressor cells (MDSCs), via inhibition of CCR2, unmasks efficacy of checkpoint blockade in GBM. Using checkpoint inhibitor-resistant murine glioma models, we show combination treatment reduces MDSCs and increases functional T cells within the tumors, and significantly extends overall survival. Our results support targeting of CCR2-expressing myeloid cells to enhance immunotherapies for GBM, and warrant translation of this approach to early human clinical trials.
Funding Information
  • HHS | NIH | National Institute of Neurological Disorders and Stroke (R01 NS108781)
  • HHS | NIH | National Cancer Institute (R01 CA195563)
  • HHS | NIH | National Cancer Institute (R35 CA197743)
  • HHS | NIH | National Cancer Institute (R01 CA208205)
  • HHS | NIH | National Cancer Institute (U01 CA224173)