The Glioma Immune Landscape: A Double-Edged Sword for Treatment Regimens

Abstract

Immune cells constitute a major part of the tumor microenvironment, thereby playing an important role in regulating tumor development. They interact with tumor cells, resulting in the suppression or promotion of glioma development. Therefore, in recent years, scientists have focused on immunotherapy that involves enhancing the immune response to fight the battle against cancer more effectively. While it has shown success against different cancer types, immunotherapy faces major roadblocks in glioma treatment. These involve the blood brain barrier, tumor heterogeneity and an immunosuppressive glioma microenvironment, among other factors. Additionally, the interaction of the peripheral immune system with the central nervous system provides another challenge for immunotherapeutic regimens. For modulating different immune cell populations to counter glioma cells, it is important to expand our knowledge about their role within the glioma microenvironment; therefore, herein, we review the different immune cell populations found in the glioma microenvironment and navigate through the various shortcomings of current immunotherapies for glioma. We conclude by providing an insight into ongoing pre-clinical and clinical trials for glioma therapies.

Keywords: clinical trials; glioblastoma therapy; glioma; immune landscape; immunotherapy.

Figure 1

Effect of tumor cells on glioma immune landscape. Glioma cells modulate immune cell functions in the tumor microenvironment, resulting in an immunosuppressive phenotype through secretion of various factors. Therefore, activation of NK and CD8+ T cell is downregulated. Further, the immunosuppressive environment is supported by macrophages polarizing to an anti-inflammatory M2 state and recruitment of MDSCs and Tregs. Created with BioRender.com (accessed on 14 March 2023).

Figure 2

Myeloid immune cells induce immunosuppression within glioma microenvironment. IFNγ—interferon gamma, Hbp1—high-mobility group box transcription factor 1, Prkar1a—protein kinase cAMP-dependent type I regulatory subunit alpha, Arg-1—arginase-1, TGF-β—transforming growth factor β, CSF1—colony stimulating factor 1. Created with BioRender.com (accessed on 14 March 2023).

Figure 3

Summary of lymphocyte response against glioma cells. (1) Glioma cells secrete placenta growth factor (PGF), which differentiates infiltrating B cells into regulatory B (Bregs) cells. (2,3) Tregs and Bregs induce an immunosuppressive environment and inhibit development of CD8+ cytotoxic T cell and its cytotoxic effect on tumor cells. Tfr cells inhibit helper and killer T cell function by secretion of PD-1, CTLA-4 and TGF-β1 signaling, while also inhibiting NK cells. NK cells lyse glioma cells by secreting granzymes and perforin. Created with BioRender.com (accessed on 14 March 2023).

Figure 4

Potential targets for glioma immunotherapy. (1) Single antigens such as GD2 or B7-H3 were targeted using CAR-T therapy in pre-clinical trials and are currently being tested as part of ongoing clinical trials. (2) Targeting multiple antigens is considered an alternative and more efficient strategy compared with targeting a single antigen in glioma therapy. (3) Targeting signaling pathways is also being tested as an alternative route in glioma therapy. GD2—disialoganglioside; B7-H3—B7 homolog 3; EphA2—ephrin receptor A2; ErbB2—erythroblastic leukemia viral oncogene homolog 2; PDGFRA—platelet derived growth factor receptor α; MMP—matrix metalloproteinases; CLEC2D—C-type lectin domain family 2 member D. Created with BioRender.com (accessed on 14 March 2023).