In this review, Jackson and Lim describe glioblastoma (GBM) as a paradigm for immune resistance mechanisms. GBM resides in an environment where immune cells are largely excluded and where tolerogenic pressure is prominent; it exhibits molecular heterogeneity, which makes it challenging to target and prone to immune escape; it often lacks obvious targetable antigens; and it expresses molecules that engage immune checkpoints. Recent strategies to target resistance in GBM include targeting multiple checkpoints, using oncolytic viruses to trigger in situ immunization, and reprogramming myeloid cells in the TME.
Glioblastoma (GBM) is the deadliest form of brain cancer, with a median survival of less than 2 years despite surgical resection, radiation, and chemotherapy. GBM's rapid progression, resistance to therapy, and inexorable recurrence have been attributed to several factors, including its rapid growth rate, its molecular heterogeneity, its propensity to infiltrate vital brain structures, the regenerative capacity of treatment-resistant cancer stem cells, and challenges in achieving high concentrations of chemotherapeutic agents in the central nervous system. Escape from immunosurveillance is increasingly recognized as a landmark event in cancer biology. Translation of this framework to clinical oncology has positioned immunotherapy as a pillar of cancer treatment. Amid the bourgeoning successes of cancer immunotherapy, GBM has emerged as a model of resistance to immunotherapy. Here we review the mechanisms of immunotherapy resistance in GBM and discuss how insights into GBM-immune system interactions might inform the next generation of immunotherapeutics for GBM and other resistant pathologies.
Author Info: (1) Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. (2) Department of Neurosurgery, The Johns Hopkins University School of Medicine
Author Info: (1) Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. (2) Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. (3) Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. mlim3@jhmi.edu.
