Immune checkpoint blockade in glioblastoma: from tumor heterogeneity to personalized treatment

Abstract

Immune checkpoint blockade (ICB) has revolutionized modern cancer therapy, arousing great interest in the neuro-oncology community. While several reports show that subsets of patients with glioma exhibit durable responses to immunotherapy, the efficacy of this treatment has not been observed for unselected patient populations, preventing its broad clinical implementation for gliomas and glioblastoma (GBM). To exploit the maximum therapeutic potential of ICB for patients with glioma, understanding the different aspects of glioma-related tumor immune responses is of critical importance. In this Review, we discuss contributing factors that distinguish subsets of patients with glioma who may benefit from ICB. Specifically, we discuss (a) the complex interaction between the tumor immune microenvironment and glioma cells as a potential influence on immunotherapy responses; (b) promising biomarkers for responses to immune checkpoint inhibitors; and (c) the potential contributions of peripheral immune cells to therapeutic responses.

Figure 1. Dynamic crosstalk between tumor and immune cells as a potential contributor to an enhanced response to immune checkpoint blockade.

Different transcriptional programs are defined by the abundance of immune cells such as macrophages, microglia, and T cells as well as the immunogenicity of tumor cells that includes the expression of MHC class I and II. In addition, the generation of a peripheral immune response following immune checkpoint inhibitors is a critical component of a successful therapeutic response.

Figure 2. Summary of the potential mechanisms that might contribute to the response to ICB.

Three potential mechanisms have been associated with better survival in patients with GBM treated with anti–PD-1 therapy: activation of the ERK1/2 cascade of the MAPK pathway; defects in the replication stress response in tumor cells; and germline POLE mutations. In addition, the mechanism underlying intratumoral Treg depletion is shown in the context of anti–CTLA-4 immunotherapy induced by antigen-dependent, cell-mediated cytotoxicity, which has been associated with germline polymorphisms of Fc-γR with high binding affinity to the therapeutic monoclonal antibodies. AP-1, activator protein 1; A-RAF, A-rapidly accelerated fibrosarcoma; ATM, ataxia telangiectasia mutated; ATR, ataxia telangiectasia and Rad3-related protein; CHK1, checkpoint kinase 1; FOSL1, Fos-related antigen 1; GRB2, growth factor receptor–bound protein 2; NF1, neurofibromin 1; SHP-2, Src homology region 2 domain–containing phosphatase-2; SOS, Son of Sevenless.