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Translational Therapeutics

Challenges in glioblastoma immunotherapy: mechanisms of resistance and therapeutic approaches to overcome them

British Journal of Cancer volume 127, pages 976–987 (2022)Cite this article

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Abstract

Glioblastoma is the most common and aggressive primary malignant brain tumour. The prognosis of patients with glioblastoma is poor, and their overall survival averages at 1 year, despite advances made in cancer therapy. The emergence of immunotherapy, a strategy that targets the natural mechanisms of immune evasion by cancerous cells, has revolutionised the treatment of melanoma, lung cancer and other solid tumours; however, immunotherapy failed to improve the prognosis of patients with glioblastoma. This is attributed to the fact that glioblastoma is endowed with numerous mechanisms of resistance that include the intrinsic resistance, which refers to the location of the tumour within the brain and the nature of the blood–brain barrier, as well as the adaptive and acquired resistance that result from the tumour heterogeneity and its immunosuppressive microenvironment. Glioblastoma is notorious for its inter and intratumoral heterogeneity, which, coupled with its spatial and temporal evolution, limits its immunogenicity. In addition, the tumour microenvironment is enriched with immunosuppressive cells and molecules that hinder the reactivity of cytotoxic immune cells and the success of immunotherapies. In this article, we review the mechanisms of resistance of glioblastoma to immunotherapy and discuss treatment strategies to overcome them worthy of further exploration.

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Fig. 1: Schematic representation of the molecules that favour the immunosuppressive tumour microenvironment in glioblastoma, and the immunotherapeutic drugs that have been investigated in clinical trials to enhance the anti-tumour response.

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Authors and Affiliations

  1. Faculty of Medicine, American University of Beirut, Beirut, Lebanon

    Karl John Habashy & Raymond Sawaya

  2. Department of Experimental Pathology, Immunology, and Microbiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon

    Rana Mansour & Michel J. Massaad

  3. Department of Neurosurgery, American University of Beirut Medical Center, Beirut, Lebanon

    Charbel Moussalem

  4. Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon

    Michel J. Massaad

  5. Center for Infectious Diseases Research, American University of Beirut, Beirut, Lebanon

    Michel J. Massaad

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MJM and KJH contributed to the conceptualisation and outline. The first draft of the manuscript was written by KJH and corrected by MJM, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. RM contributed to the figure preparation.

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Habashy, K.J., Mansour, R., Moussalem, C. et al. Challenges in glioblastoma immunotherapy: mechanisms of resistance and therapeutic approaches to overcome them. Br J Cancer 127, 976–987 (2022). https://doi.org/10.1038/s41416-022-01864-w

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