CCR2 Inhibition Reduces Tumor‐Associated Myeloid‐Derived Suppressor Cells and Unmasks an α‐PD‐1 Effect to Slow Tumor Progression in Checkpoint Inhibitor Resistant Gliomas

INTRODUCTION Immuno‐therapy directed at the PD‐1/PD‐L1 axis has yielded significant treatment advances in various human cancers. However, these outcomes have not extended to glioblastoma (GBM), with clinical trials failing to show efficacy of α‐PD‐1 monotherapy in recurrent tumors. Commonly used murine glioma models exhibit varied responsiveness to α‐PD‐1 monotherapy, e.g. GL261 gliomas are sensitive while KR158 tumors are resistant. While the mechanism by which gliomas develop resistance to PD‐1 blockade is not well defined, mounting evidence suggests infiltrating myeloid derived suppressor cells (MDSCs), characteristic of the highly immune suppressive tumor microenvironment observed in GBM, likely play a role. It has recently been shown that trafficking of these cells is dependent on the chemokine receptor 2 (CCR2) signaling axis. The current study evaluated combination of PD‐1 blockade and a novel CCR2 antagonist in α‐PD‐1 resistant gliomas. OBJECTIVE Determine if combination α‐PD‐1/CCR2 antagonist therapy is an effective treatment in α‐PD‐1 insensitive gliomas. METHODS Survival and immune cell characteristics were determined in KR158 gliomas established in either CCR2 deficient or wild type mice treated with or without PD‐1 blockade. Pharmacological antagonism of CCR2 was evaluated similarly in KR158 and 005GSC tumor bearing mice treated with CCR2 antagonist (CCX872) and/or α‐PD‐1. RESULTS CCR2 deficiency unmasked an α‐PD‐1 survival benefit in KR158 glioma bearing mice (30% durable survival [DS], P = .035). A reduction in infiltrating CD11b + /Ly6C hi MDSCs (71%, P = .039) within the tumor as well as a concomitant increase of these cells (65%, P = .020) in the bone marrow of CCR2‐deficient mice was evident. CCX872 increased median survival (MS) as a monotherapy (32 vs. 50 days, P = .002) in KR158 tumor‐bearing animals, and significantly increased DS (60% DS, P = .0005) when combined with α‐PD‐1. Similar to CCR2 deficiency, CCX872 treatment decreased MDSCs within KR158 gliomas (40%, P = .038) and increased these cells within bone marrow (74%, P = .020). In 005GSC glioma bearing mice, combination therapy enhanced MS (30 vs. 49 days, P = .005), while no monotherapy effect of CCX872 on survival was observed. CCX872 had similar effects on immune cell populations in both tumor and bone marrow of these mice. Comparison of KR158 and 005GSC gliomas revealed increased infiltration of CCR2 + cells within KR158 tumors. This result may inform the mechanism by which CCX872 had a monotherapy effect on MS only in KR158 glioma bearing animals. These data demonstrate CCX872/α‐PD‐1 synergize to enhance survival in clinically relevant glioma models via reduced MDSC infiltration, resulting in a tumor microenvironment favorable for α‐PD‐1 efficacy. CONCLUSION CCX872 and α‐PD‐1 in combination is effective in clinically relevant murine glioma models, providing a basis on which to progress this novel combinatorial treatment toward early phase human trials. Support or Funding Information Florida Center for Brain Tumor Research; Accelerate Brain Cancer Cures This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .