Kristen Giebel

Background: Glioblastoma multiforme (GBM) is the most common and aggressive primary malignant cancer of the central nervous system in adults.^1-2 Based on its histological features, the World Health Organization classifies GBM as a grade IV diffuse astrocytoma that exhibits high rates of mitotic activity, vascular proliferation, and central areas of cellular necrosis.^3-5 Through the expression of different surface receptors and secreted molecules, GBM tumor cells can modulate the phagocytic activity of tumor-associated macrophages and microglia (TAMs), leading to the alteration of various signaling pathways, including the CD47-SIRPα anti-phagocytic axis, and ultimately the promotion of tumorigenesis.³ Because of this, the efficacy of current immunotherapies against GBM cells have had a limited impact on the prognosis of patients with the median survival rate being approximately 15 months.^1-2 As a result, focus has turned to modulating the CD47-SIRPα signaling pathway with additional tumor-associated immune properties to increase the efficacy of the innate immune system and expand the number of available treatment options for those with GBM.

Objective: In this analysis, we will investigate the molecular mechanisms of development and potential immunological treatment options for those with glioblastoma multiforme.

Search Methods: A literature review was performed through online search in the PubMed database from 2018-2024 utilizing the following MeSH headings and keywords: “Glioblastoma Multiforme,” “CD47-SIRPα,” “Immunotherapy,” and “Tumor-Associated Macrophages/Microglia.”

Results: During tumorigenesis, malignant cells express an increased amount of CD47 on its surface that binds to SIRPα on TAMs, activating the CD47-SIRPα anti-phagocytic axis. Studies indicate that blockade of this interaction with anti-SIRPα antibodies allows for increased TAM-mediated phagocytosis of malignant cells.^6-7 However, sole blockade of the CD47-SIRPα signaling pathway has still led to resistance by tumor cells and therefore continued growth. As such, additional mechanisms that rely on inactivation of the CD47-SIRPα anti-phagocytic axis have been identified. A study investigating changes to the tumor cell microenvironment found that significant increases in tenascin C potentiated the phagocytic index of TAMs following complete knockout of CD47 in human and mouse models of GBM.⁸ Furthermore, a separate study explored how polarization of TAMs into different phenotypes contributes to the slowing of tumorigenesis. Following treatment with rapamycin and hydroxychloroquine, there was a significant increase in the ratio of pro-inflammatory M1 TAMs to anti-inflammatory M2 TAMs, thus promoting phagocytosis and slowing growth in GBM tumor cell models that also downregulated CD47.⁹ In the final study, GBM mouse models were treated with SIRPα-Fc alone or in combination with chloroquine to block tumor mechanisms of autophagy. When compared with SIRPα-Fc treatment alone, blocking both the CD47-SIRPα signaling pathway and autophagy significantly increased infiltration of TAMs and apoptosis of tumor cells, leading to a reduction in mean tumor weight and volume as well as an extension of median survival.¹⁰

Conclusion: The selectivity of the blood-brain barrier, tumor cell heterogeneity, and changes to the malignant microenvironment all contribute to the resistant nature of glioblastoma multiforme. As such, it is important to understand the role of these factors in immunotherapy and surveillance. Current research has shown promising results in the treatment of GBM by combining the blockade of the CD47-SIRPα signaling axis with different tumor-associated immune properties to elicit synergetic anti-tumorigenic effects that potentiate phagocytosis by TAMs. Those explored in this literature review include the increased expression of microenvironmental tenascin C, the re-education of TAMs, and the inhibition of tumor autophagy in GBM human and mouse models.

Works Cited:

1. Huang B, Li X, Li Y, Zhang J, Zong Z, Zhang H. Current Immunotherapies for Glioblastoma Multiforme. Front Immunol. 2021;11:603911. Published 2021 Mar 9. doi:10.3389/fimmu.2020.603911
2. Khabibov M, Garifullin A, Boumber Y, et al. Signaling pathways and therapeutic approaches in glioblastoma multiforme (Review). Int J Oncol. 2022;60(6):69. doi:10.3892/ijo.2022.5359
3. Geribaldi-Doldán N, Fernández-Ponce C, Quiroz RN, et al. The Role of Microglia in Glioblastoma. Front Oncol. 2021;10:603495. Published 2021 Jan 29. doi:10.3389/fonc.2020.603495
4. Schaff LR, Mellinghoff IK. Glioblastoma and Other Primary Brain Malignancies in Adults: A Review. JAMA. 2023;329(7):574-587. doi:10.1001/jama.2023.0023
5. McKinnon C, Nandhabalan M, Murray SA, Plaha P. Glioblastoma: clinical presentation, diagnosis, and management. BMJ. 2021;374:n1560. Published 2021 Jul 14. doi:10.1136/bmj.n1560
6. Kuo TC, Chen A, Harrabi O, et al. Targeting the myeloid checkpoint receptor SIRPα potentiates innate and adaptive immune responses to promote anti-tumor activity. J Hematol Oncol. 2020;13(1):160. Published 2020 Nov 30. doi:10.1186/s13045-020-00989-w
7. Hutter G, Theruvath J, Graef CM, et al. Microglia are effector cells of CD47-SIRPα antiphagocytic axis disruption against glioblastoma. Proc Natl Acad Sci U S A. 2019;116(3):997-1006. doi:10.1073/pnas.1721434116
8. Ma D, Liu S, Lal B, et al. Extracellular Matrix Protein Tenascin C Increases Phagocytosis Mediated by CD47 Loss of Function in Glioblastoma. Cancer Res. 2019;79(10):2697-2708. doi:10.1158/0008-5472.CAN-18-3125
9. Hsu SPC, Chen YC, Chiang HC, et al. Rapamycin and hydroxychloroquine combination alters macrophage polarization and sensitizes glioblastoma to immune checkpoint inhibitors. J Neurooncol. 2020;146(3):417-426. doi:10.1007/s11060-019-03360-3
10. Zhang X, Chen W, Fan J, et al. Disrupting CD47-SIRPα axis alone or combined with autophagy depletion for the therapy of glioblastoma. Carcinogenesis. 2018;39(5):689-699. doi:10.1093/carcin/bgy041