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Advance of immune checkpoint inhibitors in CNS disease

  • Jianru Sun
  • Xiangqi Shao
  • Xue Wang
  • Fan Liu

Abstract

Immune checkpoint inhibitors, innovative immunotherapies that include programmed cell death 1, programmed cell death ligand 1, and cytotoxic T lymphocyte antigen 4 inhibitors, have achieved unprecedented benefits in a variety of malignancies. Activation of immune response in body organs may cause immune-related adverse reactions involving the central nervous system. There is growing evidence that immune checkpoint plays an important role in the central nervous system. Immune checkpoints play key roles in regulating the immune response of the central nervous system in a variety of situations, and immune checkpoint modulators are promising therapeutic agents for the treatment of central nervous system disorders such as brain tumors, Alzheimer's disease, ischemic stroke, multiple sclerosis and cognitive function. Further understanding of immune checkpoints signaling of cell types such as glial cells, neurons, and peripheral immune cells in the central nervous system will provide clues to immune regulation and barrier-breaking strategies for treating brain diseases. This article will discuss the application of common immune checkpoints in the treatment of central nervous system diseases, especially programmed cell death protein-1 and cytotoxic T lymphocyte-associated protein 4.

Section

References

  1. Angelopoulou, E., Paudel, Y. N., Villa, C., Shaikh, M. F., & Piperi, C. (2020). Lymphocyte-Activation Gene 3 (LAG3) Protein as a Possible Therapeutic Target for Parkinson's Disease: Molecular Mechanisms Connecting Neuroinflammation to α-Synuclein Spreading Pathology. Biology, 9(4). doi:10.3390/biology9040086
  2. Baruch, K., Deczkowska, A., Rosenzweig, N., Tsitsou-Kampeli, A., Sharif, A. M., Matcovitch-Natan, O., . . . Schwartz, M. (2016). PD-1 immune checkpoint blockade reduces pathology and improves memory in mouse models of Alzheimer's disease. Nature Medicine, 22(2), 135-137. doi:10.1038/nm.4022
  3. Bodhankar, S., Chen, Y., Lapato, A., Dotson, A. L., Wang, J., Vandenbark, A. A., . . . Offner, H. (2015). PD-L1 Monoclonal Antibody Treats Ischemic Stroke by Controlling Central Nervous System Inflammation. Stroke, 46(10), 2926-2934. doi:10.1161/STROKEAHA.115.010592
  4. Bodhankar, S., Chen, Y., Vandenbark, A. A., Murphy, S. J., & Offner, H. (2013a). IL-10-producing B-cells limit CNS inflammation and infarct volume in experimental stroke. Metabolic Brain Disease, 28(3), 375-386. doi:10.1007/s11011-013-9413-3
  5. Bodhankar, S., Chen, Y., Vandenbark, A. A., Murphy, S. J., & Offner, H. (2013b). PD-L1 enhances CNS inflammation and infarct volume following experimental stroke in mice in opposition to PD-1. Journal of Neuroinflammation, 10, 111. doi:10.1186/1742-2094-10-111
  6. Borggrewe, M., Grit, C., Den Dunnen, W. F. A., Burm, S. M., Bajramovic, J. J., Noelle, R. J., . . . Laman, J. D. (2018). VISTA expression by microglia decreases during inflammation and is differentially regulated in CNS diseases. Glia, 66(12), 2645-2658. doi:10.1002/glia.23517
  7. Bradshaw, E. M., Chibnik, L. B., Keenan, B. T., Ottoboni, L., Raj, T., Tang, A., . . . De Jager, P. L. (2013). CD33 Alzheimer's disease locus: altered monocyte function and amyloid biology. Nature Neuroscience, 16(7), 848-850. doi:10.1038/nn.3435
  8. Brunner, M. C., Chambers, C. A., Chan, F. K., Hanke, J., Winoto, A., & Allison, J. P. (1999). CTLA-4-Mediated inhibition of early events of T cell proliferation. Journal of Immunology (Baltimore, Md. : 1950), 162(10), 5813-5820. Retrieved from https://pubmed.ncbi.nlm.nih.gov/10229815
  9. Butte, M. J., Keir, M. E., Phamduy, T. B., Sharpe, A. H., & Freeman, G. J. (2007). Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity, 27(1), 111-122. Retrieved from https://pubmed.ncbi.nlm.nih.gov/17629517
  10. Chen, S., Wu, H., Klebe, D., Hong, Y., Zhang, J., & Tang, J. (2013). Regulatory T cell in stroke: a new paradigm for immune regulation. Clinical & Developmental Immunology, 2013, 689827. doi:10.1155/2013/689827
  11. Chen, Z.-Q., Yu, H., Li, H.-Y., Shen, H.-T., Li, X., Zhang, J.-Y., . . . Chen, G. (2019). Negative regulation of glial Tim-3 inhibits the secretion of inflammatory factors and modulates microglia to antiinflammatory phenotype after experimental intracerebral hemorrhage in rats. CNS Neuroscience & Therapeutics, 25(6), 674-684. doi:10.1111/cns.13100
  12. Cuzzubbo, S., Javeri, F., Tissier, M., Roumi, A., Barlog, C., Doridam, J., . . . Carpentier, A. F. (2017). Neurological adverse events associated with immune checkpoint inhibitors: Review of the literature. European Journal of Cancer (Oxford, England : 1990), 73, 1-8. doi:10.1016/j.ejca.2016.12.001
  13. Dumas, A. A., Pomella, N., Rosser, G., Guglielmi, L., Vinel, C., Millner, T. O., . . . Marino, S. (2020). Microglia promote glioblastoma via mTOR-mediated immunosuppression of the tumour microenvironment. The EMBO Journal, 39(15), e103790. doi:10.15252/embj.2019103790
  14. Durham, N. M., Nirschl, C. J., Jackson, C. M., Elias, J., Kochel, C. M., Anders, R. A., & Drake, C. G. (2014). Lymphocyte Activation Gene 3 (LAG-3) modulates the ability of CD4 T-cells to be suppressed in vivo. PloS One, 9(11), e109080. doi:10.1371/journal.pone.0109080
  15. Efthymiou, A. G., & Goate, A. M. (2017). Late onset Alzheimer's disease genetics implicates microglial pathways in disease risk. Molecular Neurodegeneration, 12(1), 43. doi:10.1186/s13024-017-0184-x
  16. Eppihimer, M. J., Gunn, J., Freeman, G. J., Greenfield, E. A., Chernova, T., Erickson, J., & Leonard, J. P. (2002). Expression and regulation of the PD-L1 immunoinhibitory molecule on microvascular endothelial cells. Microcirculation (New York, N.Y. : 1994), 9(2), 133-145. Retrieved from https://pubmed.ncbi.nlm.nih.gov/11932780
  17. Galstyan, A., Markman, J. L., Shatalova, E. S., Chiechi, A., Korman, A. J., Patil, R., . . . Ljubimova, J. Y. (2019). Blood-brain barrier permeable nano immunoconjugates induce local immune responses for glioma therapy. Nature Communications, 10(1), 3850. doi:10.1038/s41467-019-11719-3
  18. Ghorbaninezhad, F., Masoumi, J., Bakhshivand, M., Baghbanzadeh, A., Mokhtarzadeh, A., Kazemi, T., . . . Silvestris, N. (2022). CTLA-4 silencing in dendritic cells loaded with colorectal cancer cell lysate improves autologous T cell responses in vitro. Frontiers In Immunology, 13, 931316. doi:10.3389/fimmu.2022.931316
  19. Gong, D., Shi, W., Yi, S.-j., Chen, H., Groffen, J., & Heisterkamp, N. (2012). TGFβ signaling plays a critical role in promoting alternative macrophage activation. BMC Immunology, 13, 31. doi:10.1186/1471-2172-13-31
  20. Griciuc, A., Patel, S., Federico, A. N., Choi, S. H., Innes, B. J., Oram, M. K., . . . Tanzi, R. E. (2019). TREM2 Acts Downstream of CD33 in Modulating Microglial Pathology in Alzheimer's Disease. Neuron, 103(5). doi:10.1016/j.neuron.2019.06.010
  21. Han, G., Chen, G., Shen, B., & Li, Y. (2013). Tim-3: an activation marker and activation limiter of innate immune cells. Frontiers In Immunology, 4, 449. doi:10.3389/fimmu.2013.00449
  22. Han, R., Luo, J., Shi, Y., Yao, Y., & Hao, J. (2017). PD-L1 (Programmed Death Ligand 1) Protects Against Experimental Intracerebral Hemorrhage-Induced Brain Injury. Stroke, 48(8), 2255-2262. doi:10.1161/STROKEAHA.117.016705
  23. Harada, H., Suzu, S., Hayashi, Y., & Okada, S. (2005). BT-IgSF, a novel immunoglobulin superfamily protein, functions as a cell adhesion molecule. Journal of Cellular Physiology, 204(3), 919-926. Retrieved from https://pubmed.ncbi.nlm.nih.gov/15795899
  24. Haugh, A. M., Probasco, J. C., & Johnson, D. B. (2020). Neurologic complications of immune checkpoint inhibitors. Expert Opinion On Drug Safety, 19(4), 479-488. doi:10.1080/14740338.2020.1738382
  25. Huang, J., Liu, F., Liu, Z., Tang, H., Wu, H., Gong, Q., & Chen, J. (2017). Immune Checkpoint in Glioblastoma: Promising and Challenging. Frontiers In Pharmacology, 8, 242. doi:10.3389/fphar.2017.00242
  26. Huang, X., Zhang, X., Li, E., Zhang, G., Wang, X., Tang, T., . . . Liang, T. (2020). VISTA: an immune regulatory protein checking tumor and immune cells in cancer immunotherapy. Journal of Hematology & Oncology, 13(1), 83. doi:10.1186/s13045-020-00917-y
  27. Jansen, T., Tyler, B., Mankowski, J. L., Recinos, V. R., Pradilla, G., Legnani, F., . . . Olivi, A. (2010). FasL gene knock-down therapy enhances the antiglioma immune response. Neuro-oncology, 12(5), 482-489. doi:10.1093/neuonc/nop052
  28. Johnson, D. B., Manouchehri, A., Haugh, A. M., Quach, H. T., Balko, J. M., Lebrun-Vignes, B., . . . Salem, J.-E. (2019). Neurologic toxicity associated with immune checkpoint inhibitors: a pharmacovigilance study. Journal For Immunotherapy of Cancer, 7(1), 134. doi:10.1186/s40425-019-0617-x
  29. Kao, J. C., Brickshawana, A., & Liewluck, T. (2018). Neuromuscular Complications of Programmed Cell Death-1 (PD-1) Inhibitors. Current Neurology and Neuroscience Reports, 18(10), 63. doi:10.1007/s11910-018-0878-7
  30. Kerdiles, Y. M., Stone, E. L., Beisner, D. R., McGargill, M. A., Ch'en, I. L., Stockmann, C., . . . Hedrick, S. M. (2010). Foxo transcription factors control regulatory T cell development and function. Immunity, 33(6), 890-904. doi:10.1016/j.immuni.2010.12.002
  31. Khan, E., Shrestha, A. K., Elkhooly, M., Wilson, H., Ebbert, M., Srivastava, S., . . . Sriwastava, S. (2022). CNS and PNS manifestation in immune checkpoint inhibitors: A systematic review. Journal of the Neurological Sciences, 432, 120089. doi:10.1016/j.jns.2021.120089
  32. Khan, S., & Gerber, D. E. (2020). Autoimmunity, checkpoint inhibitor therapy and immune-related adverse events: A review. Seminars In Cancer Biology, 64. doi:10.1016/j.semcancer.2019.06.012
  33. Kim, J. E., Patel, K., & Jackson, C. M. (2021). The potential for immune checkpoint modulators in cerebrovascular injury and inflammation. Expert Opinion On Therapeutic Targets, 25(2), 101-113. doi:10.1080/14728222.2021.1869213
  34. Kummer, M. P., Ising, C., Kummer, C., Sarlus, H., Griep, A., Vieira-Saecker, A., . . . Heneka, M. T. (2021). Microglial PD-1 stimulation by astrocytic PD-L1 suppresses neuroinflammation and Alzheimer's disease pathology. The EMBO Journal, 40(24), e108662. doi:10.15252/embj.2021108662
  35. Larkin, J., Chmielowski, B., Lao, C. D., Hodi, F. S., Sharfman, W., Weber, J., . . . Reardon, D. A. (2017). Neurologic Serious Adverse Events Associated with Nivolumab Plus Ipilimumab or Nivolumab Alone in Advanced Melanoma, Including a Case Series of Encephalitis. The Oncologist, 22(6), 709-718. doi:10.1634/theoncologist.2016-0487
  36. Latchman, Y., Wood, C. R., Chernova, T., Chaudhary, D., Borde, M., Chernova, I., . . . Freeman, G. J. (2001). PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nature Immunology, 2(3), 261-268. Retrieved from https://pubmed.ncbi.nlm.nih.gov/11224527
  37. Li, T., Li, J., Chen, Z., Zhang, S., Li, S., Wageh, S., . . . Zhang, H. (2022). Glioma diagnosis and therapy: Current challenges and nanomaterial-based solutions. Journal of Controlled Release : Official Journal of the Controlled Release Society, 352, 338-370. doi:10.1016/j.jconrel.2022.09.065
  38. Li, W., Wu, F., Zhao, S., Shi, P., Wang, S., & Cui, D. (2022). Correlation between PD-1/PD-L1 expression and polarization in tumor-associated macrophages: A key player in tumor immunotherapy. Cytokine & Growth Factor Reviews, 67, 49-57. doi:10.1016/j.cytogfr.2022.07.004
  39. Linsley, P. S., Greene, J. L., Brady, W., Bajorath, J., Ledbetter, J. A., & Peach, R. (1994). Human B7-1 (CD80) and B7-2 (CD86) bind with similar avidities but distinct kinetics to CD28 and CTLA-4 receptors. Immunity, 1(9), 793-801. Retrieved from https://pubmed.ncbi.nlm.nih.gov/7534620
  40. Liu, Y., & Zheng, P. (2020). Preserving the CTLA-4 Checkpoint for Safer and More Effective Cancer Immunotherapy. Trends In Pharmacological Sciences, 41(1). doi:10.1016/j.tips.2019.11.003
  41. Morisaki, Y., Ohshima, M., Suzuki, H., & Misawa, H. (2023). LAG-3 expression in microglia regulated by IFN-γ/STAT1 pathway and metalloproteases. Frontiers In Cellular Neuroscience, 17, 1308972. doi:10.3389/fncel.2023.1308972
  42. Ortler, S., Leder, C., Mittelbronn, M., Zozulya, A. L., Knolle, P. A., Chen, L., . . . Wiendl, H. (2008). B7-H1 restricts neuroantigen-specific T cell responses and confines inflammatory CNS damage: implications for the lesion pathogenesis of multiple sclerosis. European Journal of Immunology, 38(6), 1734-1744. doi:10.1002/eji.200738071
  43. Ostrom, Q. T., Bauchet, L., Davis, F. G., Deltour, I., Fisher, J. L., Langer, C. E., . . . Barnholtz-Sloan, J. S. (2014). The epidemiology of glioma in adults: a "state of the science" review. Neuro-oncology, 16(7), 896-913. Retrieved from https://pubmed.ncbi.nlm.nih.gov/24842956
  44. Qin, C., Zhou, L.-Q., Ma, X.-T., Hu, Z.-W., Yang, S., Chen, M., . . . Tian, D.-S. (2019). Dual Functions of Microglia in Ischemic Stroke. Neuroscience Bulletin, 35(5), 921-933. doi:10.1007/s12264-019-00388-3
  45. Ren, X., Akiyoshi, K., Dziennis, S., Vandenbark, A. A., Herson, P. S., Hurn, P. D., & Offner, H. (2011). Regulatory B cells limit CNS inflammation and neurologic deficits in murine experimental stroke. The Journal of Neuroscience : the Official Journal of the Society For Neuroscience, 31(23), 8556-8563. doi:10.1523/JNEUROSCI.1623-11.2011
  46. Ren, X., Akiyoshi, K., Vandenbark, A. A., Hurn, P. D., & Offner, H. (2011). Programmed death-1 pathway limits central nervous system inflammation and neurologic deficits in murine experimental stroke. Stroke, 42(9), 2578-2583. doi:10.1161/STROKEAHA.111.613182
  47. Roesch, S., Rapp, C., Dettling, S., & Herold-Mende, C. (2018). When Immune Cells Turn Bad-Tumor-Associated Microglia/Macrophages in Glioma. International Journal of Molecular Sciences, 19(2). doi:10.3390/ijms19020436
  48. Rosenzweig, N., Dvir-Szternfeld, R., Tsitsou-Kampeli, A., Keren-Shaul, H., Ben-Yehuda, H., Weill-Raynal, P., . . . Schwartz, M. (2019). PD-1/PD-L1 checkpoint blockade harnesses monocyte-derived macrophages to combat cognitive impairment in a tauopathy mouse model. Nature Communications, 10(1), 465. doi:10.1038/s41467-019-08352-5
  49. Schildberg, Frank A., Klein, Sarah R., Freeman, Gordon J., & Sharpe, Arlene H. (2016). Coinhibitory Pathways in the B7-CD28 Ligand-Receptor Family. Immunity, 44(5), 955-972. doi:10.1016/j.immuni.2016.05.002
  50. Shi, A.-P., Tang, X.-Y., Xiong, Y.-L., Zheng, K.-F., Liu, Y.-J., Shi, X.-G., . . . Zhao, J.-B. (2021). Immune Checkpoint LAG3 and Its Ligand FGL1 in Cancer. Frontiers In Immunology, 12, 785091. doi:10.3389/fimmu.2021.785091
  51. Spain, L., Walls, G., Julve, M., O'Meara, K., Schmid, T., Kalaitzaki, E., . . . Larkin, J. (2017). Neurotoxicity from immune-checkpoint inhibition in the treatment of melanoma: a single centre experience and review of the literature. Annals of Oncology : Official Journal of the European Society For Medical Oncology, 28(2), 377-385. doi:10.1093/annonc/mdw558
  52. Takahashi, T., Tagami, T., Yamazaki, S., Uede, T., Shimizu, J., Sakaguchi, N., . . . Sakaguchi, S. (2000). Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. The Journal of Experimental Medicine, 192(2), 303-310. Retrieved from https://pubmed.ncbi.nlm.nih.gov/10899917
  53. Tobias, J., Steinberger, P., Drinić, M., & Wiedermann, U. (2021). Emerging targets for anticancer vaccination: PD-1. ESMO Open, 6(5), 100278. doi:10.1016/j.esmoop.2021.100278
  54. Tomaszewski, W., Sanchez-Perez, L., Gajewski, T. F., & Sampson, J. H. (2019). Brain Tumor Microenvironment and Host State: Implications for Immunotherapy. Clinical Cancer Research : an Official Journal of the American Association For Cancer Research, 25(14), 4202-4210. doi:10.1158/1078-0432.CCR-18-1627
  55. Valencia-Sanchez, C., Sechi, E., Dubey, D., Flanagan, E. P., McKeon, A., Pittock, S. J., & Zekeridou, A. (2023). Immune checkpoint inhibitor-associated central nervous system autoimmunity. European Journal of Neurology, 30(8), 2418-2429. doi:10.1111/ene.15835
  56. van Bussel, M. T. J., Beijnen, J. H., & Brandsma, D. (2019). Intracranial antitumor responses of nivolumab and ipilimumab: a pharmacodynamic and pharmacokinetic perspective, a scoping systematic review. BMC Cancer, 19(1), 519. doi:10.1186/s12885-019-5741-y
  57. van der Merwe, P. A., Bodian, D. L., Daenke, S., Linsley, P., & Davis, S. J. (1997). CD80 (B7-1) binds both CD28 and CTLA-4 with a low affinity and very fast kinetics. The Journal of Experimental Medicine, 185(3), 393-403. Retrieved from https://pubmed.ncbi.nlm.nih.gov/9053440
  58. Vitkovic, L., Maeda, S., & Sternberg, E. (2001). Anti-inflammatory cytokines: expression and action in the brain. Neuroimmunomodulation, 9(6), 295-312. Retrieved from https://pubmed.ncbi.nlm.nih.gov/12045357
  59. Vogelgesang, A., May, V. E. L., Grunwald, U., Bakkeboe, M., Langner, S., Wallaschofski, H., . . . Dressel, A. (2010). Functional status of peripheral blood T-cells in ischemic stroke patients. PloS One, 5(1), e8718. doi:10.1371/journal.pone.0008718
  60. Wang, J., Wu, G., Manick, B., Hernandez, V., Renelt, M., Erickson, C., . . . Kalabokis, V. (2019). VSIG-3 as a ligand of VISTA inhibits human T-cell function. Immunology, 156(1), 74-85. doi:10.1111/imm.13001
  61. Wing, K., Onishi, Y., Prieto-Martin, P., Yamaguchi, T., Miyara, M., Fehervari, Z., . . . Sakaguchi, S. (2008). CTLA-4 control over Foxp3+ regulatory T cell function. Science (New York, N.Y.), 322(5899), 271-275. doi:10.1126/science.1160062
  62. Wintterle, S., Schreiner, B., Mitsdoerffer, M., Schneider, D., Chen, L., Meyermann, R., . . . Wiendl, H. (2003). Expression of the B7-related molecule B7-H1 by glioma cells: a potential mechanism of immune paralysis. Cancer Research, 63(21), 7462-7467. Retrieved from https://pubmed.ncbi.nlm.nih.gov/14612546
  63. Ye, Z., Ai, X., Yang, K., Yang, Z., Fei, F., Liao, X., . . . Zhou, S. (2023). Targeting Microglial Metabolic Rewiring Synergizes with Immune-Checkpoint Blockade Therapy for Glioblastoma. Cancer Discovery, 13(4). doi:10.1158/2159-8290.CD-22-0455
  64. Yeo, A. T., & Charest, A. (2017). Immune Checkpoint Blockade Biology in Mouse Models of Glioblastoma. Journal of Cellular Biochemistry, 118(9), 2516-2527. doi:10.1002/jcb.25948
  65. Yshii, L. M., Hohlfeld, R., & Liblau, R. S. (2017). Inflammatory CNS disease caused by immune checkpoint inhibitors: status and perspectives. Nature Reviews. Neurology, 13(12), 755-763. doi:10.1038/nrneurol.2017.144
  66. Zhao, J., Bang, S., Furutani, K., McGinnis, A., Jiang, C., Roberts, A., . . . Ji, R.-R. (2023). PD-L1/PD-1 checkpoint pathway regulates hippocampal neuronal excitability and learning and memory behavior. Neuron, 111(17). doi:10.1016/j.neuron.2023.05.022
  67. Zhao, J., Roberts, A., Wang, Z., Savage, J., & Ji, R.-R. (2021). Emerging Role of PD-1 in the Central Nervous System and Brain Diseases. Neuroscience Bulletin, 37(8), 1188-1202. doi:10.1007/s12264-021-00683-y
  68. Zhao, L., Cheng, S., Fan, L., Zhang, B., & Xu, S. (2021). TIM-3: An update on immunotherapy. International Immunopharmacology, 99, 107933. doi:10.1016/j.intimp.2021.107933

How to Cite

Sun, Jianru, et al. “Advance of Immune Checkpoint Inhibitors in CNS Disease”. Human Brain, vol. 2, no. 3, Oct. 2023, doi:10.37819/hb.3.1785.

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DOI: https://doi.org/10.37819/hb.3.1785

Published: 2023-10-25

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