Immune Escape in Glioblastoma: Mechanisms of Action and Implications for Immune Checkpoint Inhibitors and CAR T-Cell Therapy
Abstract
:Simple Summary
Abstract
1. Introduction
2. Overview of Immunotherapy
3. Glioblastoma Achieves Resistance to Immune Checkpoint Inhibitors with Unique Immune Escape Mechanisms
3.1. ICI Efficacy Is Predicated on Functional Innate and Adaptive Immunity
3.2. Glioblastoma Achieves Immune Escape in the Local Tumor Microenvironment
3.3. Glioblastoma Induces Widespread Systemic Immunosuppression
3.4. Potential Combined Approaches to Overcome the Limitations of ICIs in Glioblastoma
4. Glioblastoma Demonstrates Multiple Mechanisms of Resistance to CAR T-Cell Therapy
4.1. Glioblastoma-Induced Immunosuppression and Tumor Heterogeneity Limit the Efficacy of CAR-T Therapy
4.2. Physical Parameters and Features of Glioblastoma Present Additional Challenges to Effective CAR-T Therapy
4.3. Potential Combined Approaches to Overcome the Limitations of CAR T-Cell Therapy in Glioblastoma
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Adjunctive Treatment | Mechanism of Adjunctive Treatment | Results |
---|---|---|
Ferroptosis inhibitor (Ferrostatin-1) | ↑ M2 to M1 polarization ↑ T-cell activity | Combined treatment with a ferroptosis inhibitor and PD-1/PD-L1 blockade reversed the immunosuppressive phenotype in glioblastoma-bearing mice, resulting in prolonged survival time and reduced tumor size compared to treatment with PD-1/PD-L1 blockade alone or ferroptosis inhibition alone [52]. |
Small-molecule toosendanin | ↑ M2 to M1 polarization ↑ T-cell infiltration and activation ↓ T-cell exhaustion | a. Combined treatment with toosendanin and ICIs (anti-PD-1 and anti-CTLA-4 antibodies) delayed tumor growth and enhanced mouse survival compared to treatment with toosendanin or ICIs alone [53]. b. Combined treatment with toosendanin and CAR T-cell therapy significantly enhanced mouse survival compared to treatment with toosendanin or CAR T-cell therapy alone [53]. |
Nanostructure Nano-reshaper | ↑ number of systemic T cells ↑ local T-cell recruitment ↑ APC activity ↑ normalization of blood vessels ↑ M2 to M1 polarization | Combined treatment with Nano-reshaper and PD-1 blockade improved long-term survival in glioblastoma-bearing mice and generated immunological memory to prevent recurrence [66]. |
PHGDH inhibition | ↓ aberrant vessel sprouting ↓ intratumoral hypoxia ↑ T-cell infiltration and activity | Combined treatment with PHGDH inhibition and CAR T-cell therapy improved overall survival and delayed tumor growth compared to treatment with PHGDH inhibition or CAR T-cell therapy alone [67]. |
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Yu, C.; Hsieh, K.; Cherry, D.R.; Nehlsen, A.D.; Resende Salgado, L.; Lazarev, S.; Sindhu, K.K. Immune Escape in Glioblastoma: Mechanisms of Action and Implications for Immune Checkpoint Inhibitors and CAR T-Cell Therapy. Biology 2023, 12, 1528. https://doi.org/10.3390/biology12121528
Yu C, Hsieh K, Cherry DR, Nehlsen AD, Resende Salgado L, Lazarev S, Sindhu KK. Immune Escape in Glioblastoma: Mechanisms of Action and Implications for Immune Checkpoint Inhibitors and CAR T-Cell Therapy. Biology. 2023; 12(12):1528. https://doi.org/10.3390/biology12121528
Chicago/Turabian StyleYu, Catherine, Kristin Hsieh, Daniel R. Cherry, Anthony D. Nehlsen, Lucas Resende Salgado, Stanislav Lazarev, and Kunal K. Sindhu. 2023. "Immune Escape in Glioblastoma: Mechanisms of Action and Implications for Immune Checkpoint Inhibitors and CAR T-Cell Therapy" Biology 12, no. 12: 1528. https://doi.org/10.3390/biology12121528
APA StyleYu, C., Hsieh, K., Cherry, D. R., Nehlsen, A. D., Resende Salgado, L., Lazarev, S., & Sindhu, K. K. (2023). Immune Escape in Glioblastoma: Mechanisms of Action and Implications for Immune Checkpoint Inhibitors and CAR T-Cell Therapy. Biology, 12(12), 1528. https://doi.org/10.3390/biology12121528