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

Authors: Joseph Flores‐Toro, Defang Luo, Adithya Gopinath, Matthew R. Sarkisian, James J. Campbell, Israel Charo, Rajinder Singh, Thomas J. Schall, Meenal Datta, Rakesh K. Jain, Duane A. Mitchell, Jeffrey K. Harrison - Proceedings of the National Academy of Sciences, PNAS 2019 cited by 332

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.