Immune Escape in Glioblastoma: Mechanisms of Action and Implications for Immune Checkpoint Inhibitors and CAR T-Cell Therapy

Abstract

Glioblastoma, the most common primary brain cancer in adults, is characterized by a poor prognosis and resistance to standard treatments. The advent of immunotherapy has revolutionized the treatment of several cancers in recent years but has failed to demonstrate benefit in patients with glioblastoma. Understanding the mechanisms by which glioblastoma exerts tumor-mediated immune suppression in both the tumor microenvironment and the systemic immune landscape is a critical step towards developing effective immunotherapeutic strategies. In this review, we discuss the current understanding of immune escape mechanisms in glioblastoma that compromise the efficacy of immunotherapies, with an emphasis on immune checkpoint inhibitors and chimeric antigen receptor T-cell therapy. In parallel, we review data from preclinical studies that have identified additional therapeutic targets that may enhance overall treatment efficacy in glioblastoma when administered alongside existing immunotherapies.

Keywords: chimeric antigen receptor (CAR) T-cell therapy; glioblastoma; immune checkpoint inhibitors; immunosuppression; immunotherapy resistance; tumor immune escape; tumor microenvironment.

Figure 1

Key glioblastoma immune escape mechanisms mentioned in this review. The efficacy of immune checkpoint inhibitors (ICIs) and chimeric antigen receptor (CAR) T-cell therapy is critically dependent on an intact host immune system in both the tumor microenvironment (TME) and systemic landscape. Glioblastoma fosters an immunosuppressive environment by targeting multiple aspects of host immunity that typically should prevent cancer progression. In the tumor microenvironment, glioblastoma interferes with antigen presentation, promotes M2 macrophage polarization and Treg formation, and directly impedes T-cell cytotoxicity and proliferation. In systemic immunity, glioblastoma is associated with thymic involution and T-cell sequestration in the bone marrow. An immunosuppressive non-steroid factor further disrupts peripheral T-cell function and also impairs antigen presentation. Mechanisms of action are further described in the respective sections of this review. This figure was created with BioRender.com, access date 15 November 2023.