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 ?-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 ?-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 GBM. Outcomes will clarify the mechanism(s) by which CCR2 influences myeloid cell function within the immune-suppressed glioma microenvironment and contributes to resistance PD-1 blockade.
Current standard of care for glioblastoma (GBM) patients includes surgery, radiation, and chemotherapy but these treatment modalities are largely ineffective. Immune cells that express the chemokine receptor CCR2, gain entry to the GBM microenvironment and evidence points to a role for these cells in tumor progression and immune checkpoint inhibitor resistance. The project goals will determine the role of CCR2 in malignant brain tumors and evaluate the in vivo efficacy and mechanism of action of novel orally active brain penetrant CCR2 antagonists, using pre-clinical models of GBM and, with success, will support the use of this drug class as a new treatment option for immune checkpoint inhibitor resistant GBM patients.
