Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
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Effects of Korean red ginseng on T-cell repopulation after autologous hematopoietic stem cell transplantation in childhood cancer patients

  • Kyung Taek Hong (Department of Pediatrics, Seoul National University Children's Hospital, Seoul National University College of Medicine) ;
  • Yeon Jun Kang (Laboratory of Autoimmunity and Inflammation (LAI), Department of Biomedical Sciences, Seoul National University College of Medicine) ;
  • Jung Yoon Choi (Department of Pediatrics, Seoul National University Children's Hospital, Seoul National University College of Medicine) ;
  • Young Ju Yun (Department of Integrative Medicine, School of Korean Medicine, Pusan National University) ;
  • Il-Moo Chang (KT&G) ;
  • Hee Young Shin (Department of Pediatrics, Seoul National University Children's Hospital, Seoul National University College of Medicine) ;
  • Hyoung Jin Kang (Department of Pediatrics, Seoul National University Children's Hospital, Seoul National University College of Medicine) ;
  • Won-Woo Lee (Seoul National University Cancer Research Institute)
  • Received : 2023.06.30
  • Accepted : 2023.09.07
  • Published : 2024.01.01
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Abstract

Background: Although the survival outcomes of childhood cancer patients have improved, childhood cancer survivors suffer from various degrees of immune dysfunction or delayed immune reconstitution. This study aimed to investigate the effect of Korean Red Ginseng (KRG) on T cell recovery in childhood cancer patients who underwent autologous hematopoietic stem cell transplantation (ASCT) from the perspective of inflammatory and senescent phenotypes. Methods: This was a single-arm exploratory trial. The KRG group (n = 15) received KRG powder from month 1 to month 12 post-ASCT. We compared the results of the KRG group with those of the control group (n = 23). The proportions of T cell populations, senescent phenotypes, and cytokine production profiles were analyzed at 1, 3, 6, and 12 months post-ASCT using peripheral blood samples. Results: All patients in the KRG group completed the treatment without any safety issues and showed a comparable T cell repopulation pattern to that in the control group. In particular, KRG administration influenced the repopulation of CD4+ T cells via T cell expansion and differentiation into effector memory cell re-expressing CD45RA (EMRA) cells. Although the KRG group showed an increase in the number of CD4+ EMRA cells, the expression of senescent and exhausted markers in these cells decreased, and the capacity for senescence-related cytokine production in the senescent CD28- subset was ameliorated. Conclusions: These findings suggest that KRG promotes the repopulation of CD4+ EMRA T cells and regulates phenotypical and functional senescent changes after ASCT in pediatric patients with cancer.

Keywords

Acknowledgement

This research was supported in part by a grant related to the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI18C0998), and by a grant (grant number: 2022R1A4A1033767) from the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (MSIT).

References

  1. Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin 2023;73(1):17-48. https://doi.org/10.3322/caac.21763
  2. Park HJ, Moon EK, Yoon JY, Oh CM, Jung KW, Park BK, Shin HY, Won YJ. Incidence and survival of childhood cancer in Korea. Cancer Res Treat 2016;48(3): 869-82. https://doi.org/10.4143/crt.2015.290
  3. Landier W, Skinner R, Wallace WH, Hjorth L, Mulder RL, Wong FL, Yasui Y, Bhakta N, Constine LS, Bhatia S, et al. Surveillance for late effects in childhood cancer survivors. J Clin Oncol 2018;36(21):2216-22. https://doi.org/10.1200/JCO.2017.77.0180
  4. Ness KK, Kirkland JL, Gramatges MM, Wang Z, Kundu M, McCastlain K, LiHarms X, Zhang J, Tchkonia T, Pluijm SMF, et al. Premature physiologic aging as a paradigm for understanding increased risk of adverse Health across the lifespan of survivors of childhood cancer. J Clin Oncol 2018;36(21):2206-15. https://doi.org/10.1200/JCO.2017.76.7467
  5. Guilcher GMT, Rivard L, Huang JT, Wright NAM, Anderson L, Eissa H, Pelletier W, Ramachandran S, Schechter T, Shah AJ, et al. Immune function in childhood cancer survivors: a Children's Oncology Group review. Lancet Child Adolesc Health 2021;5(4):284-94. https://doi.org/10.1016/S2352-4642(20)30312-6
  6. Azanan MS, Abdullah NK, Chua LL, Lum SH, Abdul Ghafar SS, Kamarulzaman A, Kamaruzzaman S, Lewin SR, Woo YL, Ariffin H, et al. Immunity in young adult survivors of childhood leukemia is similar to the elderly rather than age-matched controls: role of cytomegalovirus. Eur J Immunol 2016;46(7):1715-26. https://doi.org/10.1002/eji.201646356
  7. Park JR, Kreissman SG, London WB, Naranjo A, Cohn SL, Hogarty MD, Tenney SC, Haas-Kogan D, Shaw PJ, Kraveka JM, et al. Effect of tandem autologous stem cell transplant vs single transplant on event-free survival in patients with high-risk neuroblastoma: a randomized clinical trial. JAMA 2019;322(8):746-55. https://doi.org/10.1001/jama.2019.11642
  8. Lafay-Cousin L, Dufour C. High-dose chemotherapy in children with newly diagnosed medulloblastoma. Cancers (Basel) 2022;14(3).
  9. Lee SM, Bae BS, Park HW, Ahn NG, Cho BG, Cho YL, Kwak YS. Characterization of Korean red ginseng (panax ginseng meyer): history, preparation method, and chemical composition. J Ginseng Res 2015;39(4):384-91. https://doi.org/10.1016/j.jgr.2015.04.009
  10. Hyun SH, Ahn H-Y, Kim H-J, Kim SW, So S-H. In G, Park C-K, Han C-K: immunoenhancement effects of Korean Red Ginseng in healthy adults: a randomized, double-blind, placebo-controlled trial. J Ginseng Res 2021;45(1):191-8. https://doi.org/10.1016/j.jgr.2020.08.003
  11. Lee YY, Irfan M, Quah Y, Saba E, Kim SD, Park SC, Jeong MG, Kwak YS, Rhee MH. The increasing hematopoietic effect of the combined treatment of Korean Red Ginseng and Colla corii asini on cyclophosphamide-induced immunosuppression in mice. J Ginseng Res 2021;45(5):591-8. https://doi.org/10.1016/j.jgr.2021.02.004
  12. Kim JW, Han SW, Cho JY, Chung IJ, Kim JG, Lee KH, Park KU, Baek SK, Oh SC, Lee MA, et al. Korean red ginseng for cancer-related fatigue in colorectal cancer patients with chemotherapy: a randomised phase III trial. Eur J Cancer 2020;130: 51-62. https://doi.org/10.1016/j.ejca.2020.02.018
  13. Heo JH, Lee ST, Chu K, Oh MJ, Park HJ, Shim JY, Kim M. An open-label trial of Korean red ginseng as an adjuvant treatment for cognitive impairment in patients with Alzheimer's disease. Eur J Neurol 2008;15(8):865-8. https://doi.org/10.1111/j.1468-1331.2008.02157.x
  14. Park SK, Hyun SH, Park CK, Kwak YS, Jang YJ, Kim B, Kim JH, Han CK. The antioxidant activities of Korean Red Ginseng (Panax ginseng) and ginsenosides: a systemic review through in vivo and clinical trials. J Ginseng Res 2021;45(1):41-7. https://doi.org/10.1016/j.jgr.2020.09.006
  15. Lee JM, Hah JO, Kim HS. The effect of red ginseng extract on inflammatory cytokines after chemotherapy in children. J Ginseng Res 2012;36(4):383-90. https://doi.org/10.5142/jgr.2012.36.4.383
  16. Hong KT, Kang HJ, Kim NH, Kim MS, Lee JW, Kim H, Park KD, Shin HY, Ahn HS. Successful mobilization using a combination of plerixafor and G-CSF in pediatric patients who failed previous chemomobilization with G-CSF alone and possible complications of the treatment. J Hematol Oncol 2012;5:14.
  17. Hong KT, Park HJ, Kim BK, An HY, Choi JY, Kang HJ. PTCy-based haploidentical vs matched unrelated donor peripheral blood HSCT using myeloablative targeted busulfan-based conditioning for pediatric acute leukemia. Transplant Cell Ther 2022;28(4). 195.e1-195.e7. https://doi.org/10.1016/j.jtct.2022.01.002
  18. Hong KT, Park HJ, Kim BK, An HY, Choi JY, Cheon JE, Park SH, Kim HS, Kang HJ. Favorable outcome of high-dose chemotherapy and autologous hematopoietic stem cell transplantation in patients with nonmetastatic osteosarcoma and low-degree necrosis. Front Oncol 2022;12:978949.
  19. Seers T, Vassallo P, Pollock K, Thornhill JP, Fidler S, Foster C. CD4:CD8 ratio in children with perinatally acquired HIV-1 infection. HIV Med 2018;19(9):668-72. https://doi.org/10.1111/hiv.12642
  20. Lee GH, Hong KT, Choi JY, Shin HY, Lee WW, Kang HJ. Immunosenescent characteristics of T cells in young patients following haploidentical haematopoietic stem cell transplantation from parental donors. Clin Transl Immunology 2020;9(4):e1124.
  21. Zhao Y, Shao Q, Peng G. Exhaustion and senescence: two crucial dysfunctional states of T cells in the tumor microenvironment. Cell Mol Immunol 2020;17(1):27-35. https://doi.org/10.1038/s41423-019-0344-8
  22. Jeon C, Kang S, Park S, Lim K, Hwang KW, Min H. T cell stimulatory effects of Korean red ginseng through modulation of myeloid-derived suppressor cells. J Ginseng Res 2011;35(4):462-70. https://doi.org/10.5142/jgr.2011.35.4.462
  23. Hyun SH, Ahn HY, Kim HJ, Kim SW, So SH. In G, Park CK, Han CK: immunoenhancement effects of Korean Red Ginseng in healthy adults: a randomized, double-blind, placebo-controlled trial. J Ginseng Res 2021;45(1):191-8. https://doi.org/10.1016/j.jgr.2020.08.003
  24. Laphanuwat P, Gomes DCO, Akbar AN. Senescent T cells: beneficial and detrimental roles. Immunol Rev 2023;316(1):160-75. https://doi.org/10.1111/imr.13206
  25. Effros RB, Dagarag M, Spaulding C, Man J. The role of CD8+ T-cell replicative senescence in human aging. Immunol Rev 2005;205:147-57. https://doi.org/10.1111/j.0105-2896.2005.00259.x
  26. Fagnoni FF, Vescovini R, Mazzola M, Bologna G, Nigro E, Lavagetto G, Franceschi C, Passeri M, Sansoni P. Expansion of cytotoxic CD8+ CD28- T cells in healthy ageing people, including centenarians. Immunology 1996;88(4):501-7. https://doi.org/10.1046/j.1365-2567.1996.d01-689.x
  27. Weng NP, Akbar AN, Goronzy J. CD28(-) T cells: their role in the age-associated decline of immune function. Trends Immunol 2009;30(7):306-12. https://doi.org/10.1016/j.it.2009.03.013
  28. Gustafson CE, Qi Q, Hutter-Saunders J, Gupta S, Jadhav R, Newell E, Maecker H, Weyand CM, Goronzy JJ. Immune checkpoint function of CD85j in CD8 T cell differentiation and aging. Front Immunol 2017;8:692.
  29. Yu HT, Youn JC, Kim JH, Seong YJ, Park SH, Kim HC, Lee WW, Park S, Shin EC. Arterial stiffness is associated with cytomegalovirus-specific senescent CD8(+) T cells. J Am Heart Assoc 2017;6(9).
  30. Pita-Lopez ML, Gayoso I, DelaRosa O, Casado JG, Alonso C, Munoz-Gomariz E, Tarazona R, Solana R. Effect of ageing on CMV-specific CD8 T cells from CMV seropositive healthy donors. Immun Ageing 2009;6:11.
  31. Onyema OO, Njemini R, Forti LN, Bautmans I, Aerts JL, De Waele M, Mets T. Aging-associated subpopulations of human CD8+ T-lymphocytes identified by their CD28 and CD57 phenotypes. Arch Gerontol Geriatr 2015;61(3):494-502. https://doi.org/10.1016/j.archger.2015.08.007
  32. Laznickova P, Bendickova K, Kepak T, Fric J. Immunosenescence in childhood cancer survivors and in elderly: a comparison and implication for risk stratification. Front Aging 2021;2:708788.
  33. Saule P, Trauet J, Dutriez V, Lekeux V, Dessaint JP, Labalette M. Accumulation of memory T cells from childhood to old age: central and effector memory cells in CD4(+) versus effector memory and terminally differentiated memory cells in CD8 (+) compartment. Mech Ageing Dev 2006;127(3):274-81. https://doi.org/10.1016/j.mad.2005.11.001
  34. Laznickova P, Kepak T, Hortova-Kohoutkova M, Horvath L, Sheardova K, Marciniak R, Vacca C, Siklova M, Zelante T, Rossmeislova L, et al. Childhood survivors of high-risk neuroblastoma show signs of immune recovery and not immunosenescence. Eur J Immunol 2020;50(12):2092-4. https://doi.org/10.1002/eji.202048541
  35. Verma K, Ogonek J, Varanasi PR, Luther S, Bunting I, Thomay K, Behrens YL, Mischak-Weissinger E, Hambach L. Human CD8+ CD57- TEMRA cells: too young to be called "old". PLoS One 2017;12(5):e0177405.
  36. Eberlein J, Davenport B, Nguyen T, Victorino F, Haist K, Jhun K, KarimpourFard A, Hunter L, Kedl R, Clambey ET, et al. Aging promotes acquisition of naivelike CD8+ memory T cell traits and enhanced functionalities. J Clin Invest 2016; 126(10):3942-60. https://doi.org/10.1172/JCI88546
  37. Cheng NL, Chen X, Kim J, Shi AH, Nguyen C, Wersto R, Weng NP. MicroRNA-125b modulates inflammatory chemokine CCL4 expression in immune cells and its reduction causes CCL4 increase with age. Aging Cell 2015;14(2):200-8. https://doi.org/10.1111/acel.12294