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. 2021 Jan-Dec:20:15347354211002647.
doi: 10.1177/15347354211002647.

Immunomodulatory Effect of Green Tea Treatment in Combination with Low-dose Chemotherapy in Elderly Acute Myeloid Leukemia Patients with Myelodysplasia-related Changes

Andrana K Calgarotto  1 , Ana L Longhini  1 , Fernando V Pericole de Souza  1 , Adriana S Santos Duarte  1 , Karla P Ferro  1 , Irene Santos  1 , Victor Maso  1 , Sara T Olalla Saad  1 , Cristiane Okuda Torello  1
Affiliations

Immunomodulatory Effect of Green Tea Treatment in Combination with Low-dose Chemotherapy in Elderly Acute Myeloid Leukemia Patients with Myelodysplasia-related Changes

Andrana K Calgarotto et al. Integr Cancer Ther. 2021 Jan-Dec.

Abstract

Green tea (GT) treatment was evaluated for its effect on the immune and antineoplastic response of elderly acute myeloid leukemia patients with myelodysplasia-related changes (AML-MRC) who are ineligible for aggressive chemotherapy and bone marrow transplants. The eligible patients enrolled in the study (n = 10) received oral doses of GT extract (1000 mg/day) alone or combined with low-dose cytarabine chemotherapy for at least 6 months and/or until progression. Bone marrow (BM) and peripheral blood (PB) were evaluated monthly. Median survival was increased as compared to the control cohort, though not statistically different. Interestingly, improvements in the immunological profile of patients were found. After 30 days, an activated and cytotoxic phenotype was detected: GT increased total and naïve/effector CD8+ T cells, perforin+/granzyme B+ natural killer cells, monocytes, and classical monocytes with increased reactive oxygen species (ROS) production. A reduction in the immunosuppressive profile was also observed: GT reduced TGF-β and IL-4 expression, and decreased regulatory T cell and CXCR4+ regulatory T cell frequencies. ROS levels and CXCR4 expression were reduced in bone marrow CD34+ cells, as well as nuclear factor erythroid 2-related factor 2 (NRF2) and hypoxia-inducible factor 1α (HIF-1α) expression in biopsies. Immune modulation induced by GT appears to occur, regardless of tumor burden, as soon as 30 days after intake and is maintained for up to 180 days, even in the presence of low-dose chemotherapy. This pilot study highlights that GT extracts are safe and could improve the immune system of elderly AML-MRC patients.

Keywords: acute myeloid leukemia with myelodysplasia-related changes; green tea; immune response; polyphenols; reactive oxygen species.

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Conflict of interest statement

Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.
Figure 1.
GT treatment effect on survival of elderly AML-MRC patients (n = 10) in red, compared with AML-MRC controls (n = 12), in black. The control cohort comprised patients diagnosed from December, 2008 to January, 2017 at the same Institution and attended by the same team. Log-rank test (Kaplan-Meier method). Abbreviations: AML-MRC, acute myeloid leukemia with myelodysplasia-related changes; GT, green tea; NS, non-significant.
Figure 2.
Figure 2.
GT treatment on lymphocytes and NK cells of elderly AML-MRC patients. (A-B) Frequencies of PB CD8+ T and B cells. (C) Frequencies of PB granzyme B+/perforin+ CD8+ T cells. (D-E) Frequencies of BM and PB granzyme B+ NK cells. (F) Representative gating strategy of Treg cells (double positive CD25+/FOXP3++ population selected as the percentage of CD4+ cells) by flow cytometry. (G-H) Frequencies of BM and PB Treg cells. (I) Frequencies of PB CXCR4+ Treg cells. BM and PB samples of 10 AML-MRC patients were analyzed before and after 30 days by flow cytometry. Wilcoxon test. Abbreviations: AML-MRC, acute myeloid leukemia with myelodysplasia-related changes; BM, bone marrow; GT, green tea; NK, natural killer; PB, peripheral blood; Treg, regulatory T cells.
Figure 3.
Figure 3.
GT treatment on monocytes of elderly AML-MRC patients. (A-B) Frequencies of BM and PB monocytes of 10 AML-MRC patients were analyzed before and after 30 days by flow cytometry. (C) Representative gating strategy of classical (CD14++CD16−) and intermediate/non-classical (CD14+CD16+) monocytes by flow cytometry. (D-E) Number of PB classical and non-classical monocytes from 5 AML-MRC patients analyzed before and 60 days after treatment by flow cytometry. Wilcoxon test. Abbreviations: AML-MRC, acute myeloid leukemia with myelodysplasia-related changes; BM, bone marrow; GT, green tea; PB, peripheral blood.
Figure 4.
Figure 4.
GT treatment on BM cells and biopsies of elderly AML-MRC patients. (A) ROS levels in BM CD34+ cells expressed as MFI were analyzed by flow cytometry. (B) Representative image of NRF2 expression in BM CD34+ cells analyzed by immunofluorescence microscopy. Images were collected using 63× optical zoom. (C) Representative image of NRF2 and HIF-1α protein expression in BM biopsy specimens analyzed before by immunohistochemistry using a 40× objective. BM samples of 10 AML-MRC patients were analyzed before and after 30 days of treatment. Abbreviations: AML-MRC, acute myeloid leukemia with myelodysplasia-related changes; BM, bone marrow; GT, green tea; MFI, mean fluorescence intensity; ROS, reactive oxygen species.
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