# Targeting CCR2-expressing myeloid cells to overcome immune checkpoint inhibitor resistance in glioma > **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2020 · $378,934 ## Abstract Abstract Therapeutic approaches that target the immune system in cancer are gaining traction, with agents that disrupt the PD-L1/PD-1 axis, i.e. immune checkpoint inhibitors, showing success in a growing list of malignancies. Despite preclinical studies suggesting activity of PD-1 blockade in malignant gliomas, initial clinical trial results in glioblastoma (GBM) patients have demonstrated that the majority of patients do not respond to PD-1 blockade monotherapy. These results suggest other immunosuppressive pathways operative in malignant gliomas may impart resistance to immune checkpoint inhibitors, highlighting a need for combinatorial approaches to overcome glioma-induced immunosuppression. Our studies establish that tumor infiltrative myeloid cells constitute a targetable axis within resistant gliomas. By utilizing genetic tools and clinically available inhibitors of myeloid cell trafficking and function, we aim to advance a novel combinatorial strategy which may hold relevance for effective immune checkpoint blockade in human GBM tumors. Immune suppressive myeloid-derived cells within the tumor microenvironment are a major contributor to the inability of the immune system to mount an effective anti-tumor response. As such, they constitute a promising cell type to target in order to enhance anti-tumor immune-based therapies. This project will address an important question: does inhibiting the tumor promoting activities of glioma-associated myeloid derived cells, provide a viable strategy for enhancing anti-GBM immune-based therapies? The migration and function of myeloid cells are controlled by chemokines/chemokine receptors, with the CCL2/CCR2 system being a major pathway utilized by these cells to access tissues. CCR2+ myeloid cells are present within human GBM tumors, and pre-clinical glioma models, where they exhibit immunosuppressive characteristics. We have determined that the glioma presence of these cells is dependent on CCR2. We provide compelling results that CCR2-deficiency promotes efficacy of immune checkpoint inhibitors in α-PD-1 insensitive gliomas, as well as enhanced activity in anti-PD- 1 sensitive gliomas. Moreover, treatment of glioma-bearing mice with novel CCR2 antagonists also similarly overcomes resistance of glioma to α-PD-1 inhibitory antibodies. We hypothesize that pharmacologic antagonism of CCR2 will augment the efficacy of immune targeted anti-glioma therapies by inhibiting immune suppressive myeloid-derived cells. The hypothesis will be addressed by the Aims 1) Determine the role of CCR2-expressing immune suppressive myeloid cells in PD-1 resistant glioma, 2) Determine impact of CCR2 antagonism on the adaptive immune response in PD-1 resistant glioma, and 3) Determine efficacy of CCR2 antagonists in human GBM pre-clinical models. These first ever studies will provide clear pre-clinical proof of principle for using CCR2 antagonists as an adjunctive therapeutic modality for immune checkpoint inhibitor- resistant ... ## Key facts - **NIH application ID:** 9999060 - **Project number:** 5R01NS108781-03 - **Recipient organization:** UNIVERSITY OF FLORIDA - **Principal Investigator:** Jeffrey K. Harrison - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2020 - **Award amount:** $378,934 - **Award type:** 5 - **Project period:** 2018-09-01 → 2023-08-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/9999060 ## Citation > US National Institutes of Health, RePORTER application 9999060, Targeting CCR2-expressing myeloid cells to overcome immune checkpoint inhibitor resistance in glioma (5R01NS108781-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9999060. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*