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The role of immune checkpoint receptors in the malignant phenotype of cutaneous T cell lymphoma

Abstract

Immune checkpoint receptors (ICR) modulate the immune response and are critical hubs for immunotherapy. However, data on their role in T lymphoid malignancies, such as cutaneous T cell lymphoma (CTCL), is sparse. We aimed to explore the role of ICR in the malignant features of transformed T lymphocytes and evaluate the effect of ICR-targeting monoclonal antibodies, often used as immunotherapy for solid tumors. We used the CTCL cell line HH and the Sézary cell line Hut78 to examine ICR expression and the effects of ICR inhibition on cell viability and proliferation. Despite their shared T cell progeny, the different CTCL cell lines exhibit markedly different ICR expression profiles. Programmed cell death-ligand 1 (PD-L1) was expressed by both cell lines, while programmed death-1 (PD-1) was expressed only by the HH cell line. Common to all malignant T cells was an autonomous hyper-proliferative state that did not require T cell receptor stimulation. A monoclonal antibody blocking PD-1 had a small but statistically significant augmenting effect on T cell proliferation. Of note, when the cells were exposed to ionizing radiation, healthy lymphocytes and those derived from the HH cell line were salvaged by anti-PD-L1. We show a regulatory role of ICR, mainly PD-1 and its ligand PD-L1, on cutaneous T cell malignancy.

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References

  1. Wang RF, Wang HY. “Immune targets and neoantigens for cancer immunotherapy and precision medicine.” Cell Res. 2017;27(1):11–37. https://doi.org/10.1038/cr.2016.155.

    CAS  Article  PubMed  Google Scholar 

  2. Tao JH, Cheng M, Tang JP, Liu Q, Pan F, Li XP. “Foxp3, regulatory T cell, and autoimmune diseases.” Inflammation. 2017;40(1):328–39. https://doi.org/10.1007/s10753-016-0470-8.

    CAS  Article  PubMed  Google Scholar 

  3. Callahan MK, Wolchok JD. “At the bedside: CTLA-4- and PD-1-blocking antibodies in cancer immunotherapy.” J Leukoc Biol. 2013;94(1):41–53. https://doi.org/10.1189/jlb.1212631.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. Calpe S, et al. “The SLAM and SAP gene families control innate and adaptive immune responses.” Adv Immunol. 2008;97:177–250. https://doi.org/10.1016/S0065-2776(08)00004-7.

    CAS  Article  PubMed  Google Scholar 

  5. E. Hajaj et al., “SLAMF6 deficiency augments tumor killing and skews toward an effector phenotype revealing it as a novel T cell checkpoint,” eLife, vol. 9, Mar. 2020, https://doi.org/10.7554/eLife.52539

  6. Chambers CA, Kuhns MS, Egen JG, Allison JP. “CTLA-4-mediated inhibition in regulation of T cell responses: mechanisms and manipulation in tumor immunotherapy.” Annu Re Immu. 2001;19(1):565–94. https://doi.org/10.1146/annurev.immunol.19.1.565.

    CAS  Article  Google Scholar 

  7. Camacho LH. CTLA-4 blockade with ipilimumab: biology, safety, efficacy, and future considerations. Cancer Med. May 2015;4(5):661–72. https://doi.org/10.1002/cam4.371.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. Kwok G, Yau TCC, Chiu JW, Tse E, Kwong YL. Pembrolizumab Keytruda Human Vaccines and Immunotherapeutics.Taylor and Francis Inc 2016;12(11):2777–89. https://doi.org/10.1080/21645515.2016.1199310

  9. Vanella V, Festino L, Strudel M, Simeone E, Grimaldi AM, Ascierto PA. PD-L1 inhibitors in the pipeline: promise and progress. OncoImmunology. 2018;7(1):1–11. https://doi.org/10.1080/2162402X.2017.1365209.

    Article  Google Scholar 

  10. J. Radocha, N. W. C. J. van de Donk, and K. Weisel, “Monoclonal antibodies and antibody drug conjugates in multiple myeloma,” Cancers, vol. 13, no. 7. MDPI AG, 2021. https://doi.org/10.3390/cancers13071571.

  11. R. Dada, “Program death inhibitors in classical Hodgkin’s lymphoma: a comprehensive review,” Annals of Hematology, vol. 97, no. 4. Springer Verlag, pp. 555–561, 2018. https://doi.org/10.1007/s00277-017-3226-0.

  12. Willemze R, et al. “WHO-EORTC classification for cutaneous lymphomas.” Blood. 2005;105(10):3768–85. https://doi.org/10.1182/blood-2004-09-3502.

    CAS  Article  PubMed  Google Scholar 

  13. Samimi S, et al. Increased programmed death-1 expression on CD4+ T cells in cutaneous T-cell lymphoma: implications for immune suppression. Arch Dermatol. Dec. 2010;146(12):1382–8. https://doi.org/10.1001/archdermatol.2010.200.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. Çetinözman F, Jansen PM, Vermeer MH, Willemze R. Differential expression of Programmed Death-1 (PD-1) in Sézary syndrome and mycosis fungoides. Arch Dermatol. Dec. 2012;148(12):1379–85. https://doi.org/10.1001/archdermatol.2012.2089.

    Article  PubMed  Google Scholar 

  15. Saulite I, et al. Blockade of programmed cell death protein 1 (PD-1) in Sézary syndrome reduces Th2 phenotype of non-tumoral T lymphocytes but may enhance tumor proliferation. Oncoimuunology. Mar. 2020;9(1):1738797. https://doi.org/10.1080/2162402X.2020.1738797.

    Article  Google Scholar 

  16. Kantekure K, et al. Expression patterns of the immunosuppressive proteins PD-1/CD279 and PD-L1/CD274 at different stages of cutaneous T-cell lymphoma/mycosis fungoides. Am J Dermatopathol. Feb. 2012;34(1):126–8. https://doi.org/10.1097/DAD.0b013e31821c35cb.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Wong HK, et al. Increased expression of CTLA-4 in malignant T cells from patients with mycosis fungoides - cutaneous T-cell lymphoma. J Investig Dermatol. Jan. 2006;126(1):212–9. https://doi.org/10.1038/sj.jid.5700029.

    CAS  Article  PubMed  Google Scholar 

  18. D. M. Weiner, J. S. Durgin, M. Wysocka, and A. H. Rook, “The immunopathogenesis and immunotherapy of cutaneous T cell lymphoma: current and future approaches,” Journal of the American Academy of Dermatology, vol. 84, no. 3. Mosby Inc., pp. 597–604, 01, 2021. https://doi.org/10.1016/j.jaad.2020.12.026

  19. Serrels A, et al. Nuclear FAK controls chemokine transcription, tregs, and evasion of anti-tumor immunity. Cell. Sep. 2015;163(1):160–73. https://doi.org/10.1016/j.cell.2015.09.001.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. L. Agresta, K. H. N. Hoebe, and E. M. Janssen, “The emerging role of CD244 signaling in immune cells of the tumor microenvironment,” Frontiers in Immunology, vol. 9, no. NOV. Frontiers Media S.A., Nov. 28, 2018. https://doi.org/10.3389/fimmu.2018.02809.

  21. G. Pawelec, “Is there a positive side to T cell exhaustion?,” Frontiers in Immunology, vol. 10, no. JAN. Frontiers Media S.A., p. 111, Jan. 29, 2019. https://doi.org/10.3389/fimmu.2019.00111.

  22. Janiga J, Kentley J, Nabhan C, Abdulla F. “Current systemic therapeutic options for advanced mycosis fungoides and Sézary syndrome.” Leukemia and Lymphoma. 2018;59(3):562–77. https://doi.org/10.1080/10428194.2017.1347650.

    CAS  Article  PubMed  Google Scholar 

  23. Oka T, et al. Serum soluble CD48 levels as a prognostic marker in mycosis fungoides and Sézary syndrome. J Invest Dermatol. Oct 2018;138(10):2286–8. https://doi.org/10.1016/j.jid.2018.03.1519.

    CAS  Article  PubMed  Google Scholar 

  24. Hansen ER, et al. Leukemic T cells from patients with cutaneous T-cell lymphoma demonstrate enhanced activation through CDw60, CD2, and CD28 relative to activation through the T-cell antigen receptor complex. J Investig Dermatol. 1993;100(5):667–73. https://doi.org/10.1111/1523-1747.ep12472333.

    CAS  Article  PubMed  Google Scholar 

  25. Mazzeo E, et al. “The current management of mycosis fungoides and Sézary syndrome and the role of radiotherapy: principles and indications.” Reports of Practical Oncology and Radiotherapy. 2014;19(2):77–91.

    Article  Google Scholar 

  26. Khodadoust MS, et al. “Pembrolizumab in relapsed and refractory mycosis fungoides and Sézary syndrome: a multicenter phase II study.” JCO. 2019;38(1):20–8. https://doi.org/10.1200/JCO.19.01056.

    Article  Google Scholar 

  27. Lesokhin AM, et al. “Nivolumab in patients with relapsed or refractory hematologic malignancy: preliminary results of a phase Ib study.” J Clin Oncology. 2016;34(23):2698–704. https://doi.org/10.1200/JCO.2015.65.9789.

    CAS  Article  Google Scholar 

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Correspondence to Rony Shreberk-Hassidim.

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Shreberk-Hassidim, R., Geiger-Maor, A., Eisenberg, G. et al. The role of immune checkpoint receptors in the malignant phenotype of cutaneous T cell lymphoma. Immunol Res (2022). https://doi.org/10.1007/s12026-022-09308-6

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  • DOI: https://doi.org/10.1007/s12026-022-09308-6

Keywords

  • Immune checkpoint receptors
  • Cutaneous T cell lymphoma
  • Programmed death receptor ligand-1 (PDL-1)
  • Immunotherapy
  • Programmed death-1 (PD-1)