Effects of Korean red ginseng on T-cell repopulation after autologous hematopoietic stem cell transplantation in childhood cancer patients

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: Autologous hematopoietic stem cell transplantation; Childhood; Immunosenescence; Korea red ginseng; T cells.

Graphical abstract

Fig. 1

Effect of KRG treatment on the repopulation of T cells following ASCT. (A, B) Absolute number of CD3⁺, CD4⁺, and CD8⁺ T cells in the control and KRG-treated patients after ASCT. (C) Ratio of CD4⁺ to CD8⁺ T cells in both groups. (D, E) Phenotypic analysis of T cells in freshly-isolated PBMC samples by flow cytometry. Distribution of functional CD4⁺ and CD8⁺ T cell subsets is defined by CD45RA and CCR7 expression: naive (CD45RA⁺CCR7⁺), central memory (CM; CD45RA⁻CCR7⁺), effector memory (EM; CD45RA⁻CCR7^-), and CD45RA⁺ effector memory (EMRA; CD45RA⁺CCR7^-). Representative FACS plot of functional T cell subsets at 12 months post-ASCT (left) and time-dependent changes in the frequency of each subset (right) are shown. (F, G) Absolute number of functional T cells in the CD4⁺ and CD8⁺ subsets. Bar graphs show the mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001 as determined by one-way ANOVA. †P < 0.05 as determined by two-tailed unpaired non-parametric t-test.

Fig. 2

Effect of KRG treatment on the senescent phenotypes of T cells following ASCT. (A) Time-dependent changes in the frequency of CD28^- cells among CD4⁺ and CD8⁺ T cells during the 12 months after ASCT were determined by flow cytometry. (B) Time-dependent changes in the frequency of naive, CM, EM, and EMRA subsets of CD4⁺CD28^- (left) and CD8⁺CD28^- (right) T cells in the control and KRG-treated patients. (C, D) Changes in the expression of senescence markers in the EM and EMRA subsets of CD4⁺ and CD8⁺ T cells. Frequency (%) of CD28^-, CD57⁺, CD85j⁺, or CD28⁻CD57⁺ cells in the EM and EMRA subsets of CD4⁺ and CD8⁺ T cells in both patient groups. Bar and line graphs show the mean ± SEM. Orange- or pale blue-colored p-values and asterisks were analyzed for the KGR or control group. Black-colored p-values and crosses were analyzed and compared at each time point between the KGR and control groups. **P < 0.01, ***P < 0.001, and ****P < 0.0001 as determined by one-way ANOVA. †P < 0.05, ††P < 0.01, and †††P < 0.001 as determined by two-tailed unpaired non-parametric t-test.

Fig. 3

Cytokine production profiles of senescent CD28^-T cells. PBMCs of patients were stimulated with PMA and ionomycin for 6 h (n = 8 ∼ 18 for each time point), followed by intracellular cytokine staining (ICS). (A) Representative FACS plot of cytokine-producing CD4⁺ and CD8⁺ T cells following ASCT in the control and KRG-treated patients at 1-month post-ASCT. (B) Time-dependent changes in the frequency (%) of cytokine-producing CD4⁺ (left) and CD8⁺ (right) T cells. (C) Representative FACS plot of cytokine-producing CD28⁺ or CD28^- cells in the CD4⁺ and CD8⁺ populations at 1-month post-ASCT. (D) Frequency (%) of cytokine-producing CD28⁺ or CD28^- cells in CD4⁺ and CD8⁺ populations in the control and KRG-treated patients at 1 and 12 months after ASCT. Bar and line graphs show the mean ± S.E.M. †P < 0.05, ††P < 0.01, and †††P < 0.001 as determined by two-tailed unpaired non-parametric t-test.