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Small Molecule Inhibition of Glycogen Synthase Kinase-3 in Cancer Immunotherapy

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Human Cell Transformation

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1164))

Abstract

Immune checkpoint blockade (ICB) has proved successful in the immunotherapeutic treatment of various human cancers. Despite its success, most patients are still not cured while immunogenic cold cancers are still poorly responsive. There is a need for novel clinical interventions in immunotherapy, either alone or in conjunction with ICB. Here, we outline our recent discovery that the intracellular signaling kinase glycogen synthase kinase-3 (GSK-3) is a central regulator of PD-1 in T-cells. We demonstrate the application of small molecule inhibitor (SMI) approaches to down-regulate PD-1 in tumor immunotherapy. GSK-3 SMIs were found as effective as anti-PD-1 in the elimination of melanoma in mouse models. We propose the development of novel SMIs to target co-receptors for the future of immunotherapy.

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References

  1. Page, D. B., et al. (2014). Immune modulation in cancer with antibodies. Annual Review of Medicine, 65, 185–202.

    Article  CAS  Google Scholar 

  2. Pentcheva-Hoang, T., et al. (2014). Cytotoxic T lymphocyte antigen-4 blockade enhances antitumor immunity by stimulating melanoma-specific T-cell motility. Cancer Immunology Research, 2(10), 970–980.

    Article  CAS  Google Scholar 

  3. Sharma, P., et al. (2011). Novel cancer immunotherapy agents with survival benefit: Recent successes and next steps. Nature Reviews. Cancer, 11(11), 805–812.

    Article  CAS  Google Scholar 

  4. Schildberg, F. A., et al. (2016). Coinhibitory pathways in the B7-CD28 ligand-receptor family. Immunity, 44(5), 955–972.

    Article  CAS  Google Scholar 

  5. Baumeister, S. H., et al. (2016). Coinhibitory pathways in immunotherapy for cancer. Annual Review of Immunology, 34, 539–573.

    Article  CAS  Google Scholar 

  6. Iwai, Y., et al. (2002). Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proceedings of the National Academy of Sciences of the United States of America, 99(19), 12293–12297.

    Article  CAS  Google Scholar 

  7. Freeman, G. J., et al. (2000). Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. The Journal of Experimental Medicine, 192(7), 1027–1034.

    Article  CAS  Google Scholar 

  8. Okazaki, T., Iwai, Y., & Honjo, T. (2002). New regulatory co-receptors: Inducible co-stimulator and PD-1. Current Opinion in Immunology, 14(6), 779–782.

    Article  CAS  Google Scholar 

  9. Latchman, Y., et al. (2001). PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nature Immunology, 2(3), 261–268.

    Article  CAS  Google Scholar 

  10. Barber, D. L., et al. (2006). Restoring function in exhausted CD8 T cells during chronic viral infection. Nature, 439(7077), 682–687.

    Article  CAS  Google Scholar 

  11. Day, C. L., et al. (2006). PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature, 443(7109), 350–354.

    Article  CAS  Google Scholar 

  12. Topalian, S. L., et al. (2012). Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. The New England Journal of Medicine, 366(26), 2443–2454.

    Article  CAS  Google Scholar 

  13. Wolchok, J. D., et al. (2013). Nivolumab plus ipilimumab in advanced melanoma. The New England Journal of Medicine, 369(2), 122–133.

    Article  CAS  Google Scholar 

  14. Wherry, E. J., et al. (2007). Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity, 27(4), 670–684.

    Article  CAS  Google Scholar 

  15. Ahmadzadeh, M., et al. (2009). Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood, 114(8), 1537–1544.

    Article  CAS  Google Scholar 

  16. Ghebeh, H., et al. (2006). The B7-H1 (PD-L1) T lymphocyte-inhibitory molecule is expressed in breast cancer patients with infiltrating ductal carcinoma: Correlation with important high-risk prognostic factors. Neoplasia, 8(3), 190–198.

    Article  CAS  Google Scholar 

  17. Staron, M. M., et al. (2014). The transcription factor FoxO1 sustains expression of the inhibitory receptor PD-1 and survival of antiviral CD8(+) T cells during chronic infection. Immunity, 41(5), 802–814.

    Article  CAS  Google Scholar 

  18. Oestreich, K. J., et al. (2008). NFATc1 regulates PD-1 expression upon T cell activation. Journal of Immunology, 181(7), 4832–4839.

    Article  CAS  Google Scholar 

  19. Mathieu, M., et al. (2013). Notch signaling regulates PD-1 expression during CD8(+) T-cell activation. Immunology and Cell Biology, 91(1), 82–88.

    Article  CAS  Google Scholar 

  20. Xiao, G., et al. (2012). Activator protein 1 suppresses antitumor T-cell function via the induction of programmed death 1. Proceedings of the National Academy of Sciences of the United States of America, 109(38), 15419–15424.

    Article  CAS  Google Scholar 

  21. Weiss, A., & Littman, D. R. (1994). Signal transduction by lymphocyte antigen receptors. Cell, 76(2), 263–274.

    Article  CAS  Google Scholar 

  22. Rudd, C. E. (1999). Adaptors and molecular scaffolds in immune cell signaling. Cell, 96(1), 5–8.

    Article  CAS  Google Scholar 

  23. Rudd, C. E., et al. (1988). The CD4 receptor is complexed in detergent lysates to a protein-tyrosine kinase (pp58) from human T lymphocytes. Proceedings of the National Academy of Sciences of the United States of America, 85(14), 5190–5194.

    Article  CAS  Google Scholar 

  24. Barber, E. K., et al. (1989). The CD4 and CD8 antigens are coupled to a protein-tyrosine kinase (p56lck) that phosphorylates the CD3 complex. Proceedings of the National Academy of Sciences of the United States of America, 86(9), 3277–3281.

    Article  CAS  Google Scholar 

  25. Veillette, A., et al. (1989). Signal transduction through the CD4 receptor involves the activation of the internal membrane tyrosine-protein kinase p56lck. Nature, 338(6212), 257–259.

    Article  CAS  Google Scholar 

  26. Chan, A. C., et al. (1992). ZAP-70: A 70 kd protein-tyrosine kinase that associates with the TCR zeta chain. Cell, 71(4), 649–662.

    Article  CAS  Google Scholar 

  27. Woodgett, J. R. (1990). Molecular cloning and expression of glycogen synthase kinase-3/factor A. The EMBO Journal, 9(8), 2431–2438.

    Article  CAS  Google Scholar 

  28. Cohen, P., & Frame, S. (2001). The renaissance of GSK3. Nature Reviews. Molecular Cell Biology, 2(10), 769–776.

    Article  CAS  Google Scholar 

  29. Beals, C. R., et al. (1997). Nuclear export of NF-ATc enhanced by glycogen synthase kinase-3. Science, 275, 1930–1934.

    Article  CAS  Google Scholar 

  30. Neal, J. W., & Clipstone, N. A. (2001). Glycogen synthase kinase-3 inhibits the DNA binding activity of NFATc. The Journal of Biological Chemistry, 276, 3666–3673.

    Article  CAS  Google Scholar 

  31. Ohteki, T., et al. (2000). Negative regulation of T cell proliferation and interleukin 2 production by the serine threonine kinase GSK-3. The Journal of Experimental Medicine, 192(1), 99–104.

    Article  CAS  Google Scholar 

  32. Wood, J. E., Schneider, H., & Rudd, C. E. (2006). TcR and TcR-CD28 engagement of protein kinase B (PKB/AKT) and glycogen synthase kinase-3 (GSK-3) operates independently of guanine nucleotide exchange factor VAV-1. The Journal of Biological Chemistry, 281(43), 32385–32394.

    Article  CAS  Google Scholar 

  33. Appleman, L. J., et al. (2002). CD28 costimulation mediates down-regulation of p27kip1 and cell cycle progression by activation of the PI3K/PKB signaling pathway in primary human T cells. Journal of Immunology, 168(6), 2729–2736.

    Article  CAS  Google Scholar 

  34. Jope, R. S., & Roh, M. S. (2006). Glycogen synthase kinase-3 (GSK3) in psychiatric diseases and therapeutic interventions. Current Drug Targets, 7(11), 1421–1434.

    Article  CAS  Google Scholar 

  35. Mazanetz, M. P., & Fischer, P. M. (2007). Untangling tau hyperphosphorylation in drug design for neurodegenerative diseases. Nature Reviews. Drug Discovery, 6(6), 464–479.

    Article  CAS  Google Scholar 

  36. Taylor, A., et al. (2016). Glycogen synthase kinase 3 inactivation drives T-bet-mediated downregulation of co-receptor PD-1 to enhance CD8(+) cytolytic T cell responses. Immunity, 44(2), 274–286.

    Article  CAS  Google Scholar 

  37. Taylor, A., Rothstein, D., & Rudd, C. E. (2018). Small molecule inhibition of PD-1 transcription is an effective alternative to antibody blockade in cancer therapy. Cancer Research, 78, 706–717.

    Article  CAS  Google Scholar 

  38. Taylor, A., & Rudd, C. E. (2017). Glycogen synthase kinase 3 inactivation compensates for the lack of CD28 in the priming of CD8+ cytotoxic T-cells: Implications for anti-PD-1 immunotherapy. Frontiers in Immunology, 8, 1653.

    Article  Google Scholar 

  39. Aranda, F., et al. (2011). Adjuvant combination and antigen targeting as a strategy to induce polyfunctional and high-avidity T-cell responses against poorly immunogenic tumors. Cancer Research, 71(9), 3214–3224.

    Article  CAS  Google Scholar 

  40. Zhu, Q., et al. (2011). Suppression of glycogen synthase kinase 3 activity reduces tumor growth of prostate cancer in vivo. Prostate, 71(8), 835–845.

    Article  CAS  Google Scholar 

  41. Klein, P. S., & Melton, D. A. (1996). A molecular mechanism for the effect of lithium on development. Proceedings of the National Academy of Sciences of the United States of America, 93(16), 8455–8459.

    Article  CAS  Google Scholar 

  42. Piazza, F., et al. (2010). Glycogen synthase kinase-3 regulates multiple myeloma cell growth and bortezomib-induced cell death. BMC Cancer, 10, 526.

    Article  CAS  Google Scholar 

  43. Dickey, A., et al. (2011). GSK-3beta inhibition promotes cell death, apoptosis, and in vivo tumor growth delay in neuroblastoma Neuro-2A cell line. Journal of Neuro-Oncology, 104(1), 145–153.

    Article  CAS  Google Scholar 

  44. Beurel, E., et al. (2009). Glycogen synthase kinase-3 inhibitors augment TRAIL-induced apoptotic death in human hepatoma cells. Biochemical Pharmacology, 77(1), 54–65.

    Article  CAS  Google Scholar 

  45. Finke, J. H., et al. (1993). Loss of T-cell receptor zeta chain and p56lck in T-cells infiltrating human renal cell carcinoma. Cancer Research, 53(23), 5613–5616.

    CAS  PubMed  Google Scholar 

  46. Rayman, P., et al. (2000). Tumor-induced dysfunction in interleukin-2 production and interleukin-2 receptor signaling: A mechanism of immune escape. The Cancer Journal from Scientific American, 6(Suppl 1), S81–S87.

    PubMed  Google Scholar 

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Acknowledgements

C.E.R. was supported by Wellcome Trust 092627/Z/10/Z, and CER and AT were supported by CRUK grant A20105. We thank Dr. Jim Woodgett, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, for the heterozygotes of the GSK-3α/β conditional knockout mice. PD-1-deficient mice (Pdcd1−/−) were a kind gift of Prof. T. Honjo, Kyoto University Faculty of Medicine, Japan.

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Authors and Affiliations

  1. Division of Haematology and Immunology, Leeds Institute of Medical Research, Leeds, UK

    Alison Taylor

  2. Division of Immunology-Oncology Research Center, Maisonneuve-Rosemont Hospital, Montreal, QC, Canada

    Christopher E. Rudd

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  1. Alison Taylor
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  2. Christopher E. Rudd
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Correspondence to Christopher E. Rudd .

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Editors and Affiliations

  1. Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA

    Johng S. Rhim

  2. Georgetown University Medical Center, Washington, DC, USA

    Anatoly Dritschilo

  3. Department of Medicine, McGill University Health Centre, Montréal, QC, Canada

    Richard Kremer

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Taylor, A., Rudd, C.E. (2019). Small Molecule Inhibition of Glycogen Synthase Kinase-3 in Cancer Immunotherapy. In: Rhim, J., Dritschilo, A., Kremer, R. (eds) Human Cell Transformation. Advances in Experimental Medicine and Biology, vol 1164. Springer, Cham. https://doi.org/10.1007/978-3-030-22254-3_17

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