scholarly journals Breast Cancer Cells and PD-1/PD-L1 Blockade Upregulate the Expression of PD-1, CTLA-4, TIM-3 and LAG-3 Immune Checkpoints in CD4+ T Cells

Vaccines ◽  
2019 ◽  
Vol 7 (4) ◽  
pp. 149 ◽  
Author(s):  
Saleh ◽  
Toor ◽  
Khalaf ◽  
Elkord
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
T Cell ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Checkpoint Inhibitors ◽  
T Cell Subsets ◽  
Cd4 T Cell ◽  
Immune Checkpoints ◽  
Tnbc Cell

: Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype, and it exhibits resistance to common breast cancer therapies. Immune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD-1) and its ligand, PD-L1, have been approved to treat various cancers. However, the therapeutic efficacy of targeting PD-1/PD-L1 axis in breast cancer is under clinical investigation. In addition, the mechanisms of action of drugs targeting PD-1 and PD-L1 have not been fully elucidated. In this study, we investigated the effect of human TNBC cell lines, MDA-MB-231 and MDA-MB-468, and the non-TNBC cell line, MCF-7, on the expression of immune checkpoints (ICs) on CD4+ T cell subsets, including regulatory T cells (Tregs), using a co-culture system. We also examined the effect of blocking PD-1 or PD-L1 separately and in combination on IC expression by CD4+ T cell subsets. We found that breast cancer cells upregulate the expression of ICs including PD-1, cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) and lymphocyte activation gene-3 (LAG-3) in CD4+ T cell subsets. We also found that the co-blockade of PD-1 and PD-L1 further upregulates the co-expression of TIM-3 and LAG-3 on CD4+CD25+ T cells and CD4+CD25+FoxP3+Helios+ Tregs in the presence of TNBC cells, but not in non-TNBC cells. Our results indicate the emergence of compensatory inhibitory mechanisms, most likely mediated by Tregs and activated non-Tregs, which could lead to the development of TNBC resistance against PD-1/PD-L1 blockade.

scholarly journals CD4 T-cell immune stimulation of HER2+ breast cancer cells alters response to trastuzumab in vitro

2020 ◽  
Author(s):  
Patrick Song ◽  
Amer Mansur ◽  
Kari J. Dugger ◽  
Tessa R. Davis ◽  
Grant Howard ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
T Cell ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Receptor Expression ◽  
Immune Stimulation ◽  
Her2 Breast Cancer ◽  
Stimulation Of

Abstract Introduction: The HER2+ tumor immune microenvironment is composed of macrophages, natural killer cells, and tumor infiltrating lymphocytes, which produce pro-inflammatory cytokines. Determining the effect of T-cells on HER2+ cancer cells during therapy could guide immunogenic therapies that trigger antibody-dependent cellular cytotoxicity. This study utilized longitudinal in vitro time-resolved microscopy imaging to measure T-cell influence on trastuzumab in HER2+ breast cancer.Methods: Fluorescently-labeled breast cancer cells (BT474, SKBR3, MDA-MB-453, and MDA-MB-231) were co-cultured with CD4+ T-cells (Jurkat cell line) and longitudinally imaged to quantify cancer cell viability when treated with or without trastuzumab (10, 25, 50 and 100 mg/mL). The presence and timing of T-cell co-culturing was manipulated to determine immune stimulation of trastuzumab-treated HER2+ breast cancer. HER2 and TNF-a expression were evaluated with western blot and ELISA, respectively. Significance was calculated using a two-tailed parametric t-test. Results: The viability of HER2+ cancer cells significantly decreased when exposed to 25 mg/mL trastuzumab and T-cells, compared to cancer cells exposed to trastuzumab without T-cells (p = 0.01). The presence of T-cells significantly increased TNF-a expression in trastuzumab-treated cancer cells (p = 0.02). Conversely, cancer cells treated with TNF-a and trastuzumab had a similar decrease in viability as trastuzumab-treated cancer cells co-cultured with T-cells (p = 0.32).Conclusions: The presence of T-cells significantly increases the efficacy of targeted therapies and suggests trastuzumab may trigger immune mediated cytotoxicity. Increased TNF-a receptor expression suggest cytokines may interact with trastuzumab to create a state of enhanced response to therapy in HER2+ breast cancer, which has potential to reducing tumor burden.

scholarly journals CD4 T-cell immune stimulation of HER2 + breast cancer cells alters response to trastuzumab in vitro

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Patrick N. Song ◽  
Ameer Mansur ◽  
Kari J. Dugger ◽  
Tessa R. Davis ◽  
Grant Howard ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
T Cell ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Immune Stimulation ◽  
Her2 Breast Cancer ◽  
Tnf Α ◽  
Stimulation Of

Abstract Introduction The HER2 + tumor immune microenvironment is composed of macrophages, natural killer cells, and tumor infiltrating lymphocytes, which produce pro-inflammatory cytokines. Determining the effect of T-cells on HER2 + cancer cells during therapy could guide immunogenic therapies that trigger antibody-dependent cellular cytotoxicity. This study utilized longitudinal in vitro time-resolved microscopy to measure T-cell influence on trastuzumab in HER2 + breast cancer. Methods Fluorescently-labeled breast cancer cells (BT474, SKBR3, MDA-MB-453, and MDA-MB-231) were co-cultured with CD4 + T-cells (Jurkat cell line) and longitudinally imaged to quantify cancer cell viability when treated with or without trastuzumab (10, 25, 50 and 100 μg/mL). The presence and timing of T-cell co-culturing was manipulated to determine immune stimulation of trastuzumab-treated HER2 + breast cancer. HER2 and TNF-α expression were evaluated with western blot and ELISA, respectively. Significance was calculated using a two-tailed parametric t-test. Results The viability of HER2 + cancer cells significantly decreased when exposed to 25 μg/mL trastuzumab and T-cells, compared to cancer cells exposed to trastuzumab without T-cells (p = 0.01). The presence of T-cells significantly increased TNF-α expression in trastuzumab-treated cancer cells (p = 0.02). Conversely, cancer cells treated with TNF-α and trastuzumab had a similar decrease in viability as trastuzumab-treated cancer cells co-cultured with T-cells (p = 0.32). Conclusions The presence of T-cells significantly increases the efficacy of targeted therapies and suggests trastuzumab may trigger immune mediated cytotoxicity. Increased TNF-α receptor expression suggest cytokines may interact with trastuzumab to create a state of enhanced response to therapy in HER2 + breast cancer, which has potential to reducing tumor burden.

scholarly journals Specifically Targeting the Interface Between HER1-HER3 Heterodimer on Breast Cancer to Limit Off-Target Effects Using Chimeric Antigen Receptor Designs with Improved T-Cell Energy Balance

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2151-2151
Author(s):  
Bipulendu Jena ◽  
Natalya Belousova ◽  
George T McNamara ◽  
David Rushworth ◽  
Tiejuan Mi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
T Cell ◽  
Cancer Cells ◽  
Chimeric Antigen Receptor ◽  
Breast Cancer Cells ◽  
Genetically Modified ◽  
Car T Cells ◽  
Car T ◽  
Egfr Family

Abstract Human epidermal growth factor receptor (EGFR) family consists of four members i.e. EGFR (HER1), HER2 (ErbB2), HER3 (ErbB3,) and HER4 (ErbB4). Overexpression, mutation, or catalytic activation of these proteins can lead to malignancies in breast, ovarian, colorectal, pancreatic and lung. Therapies targeting EGFR-associated proteins to disrupt signaling may fail because of crosstalk within the EGFR family or among downstream pathways. One mechanism of escape is HER3 activation and concomitant heterodimer formation with HER1 causing disease relapse and treatment failure. A bi-specific monoclonal antibody (mAb, MEHD7945A) can specifically bind an epitope shared between HER1-HER3 heterodimer thereby blocking EGFR-HER3 mediated signaling (Schaefer et al., Cancer Cell, 2011). We now report that the specificity of this mAb can be used to redirect the specificity of T cells through enforced expression of a chimeric antigen receptor (CAR) targeting the HER1-HER3 heterodimer, such as expressed on breast cancer cells. A 2nd generation CAR targeting the HER1-HER3 heterodimer was expressed from DNA plasmid constituting scFv (designated DL11f, derived from mAb MEHD7945A) coupled to CD3-zeta fused in frame with chimeric CD28 or CD137 T-cell signaling domains on a clinical-grade Sleeping Beauty (SB) backbone. T cells were electroporated with SB system and numerically expanded on irradiated “universal” activating and propagating cells (uAaPC) (Rushworth et al., J Immunotherapy, 2014). These feeder cells are derived from K-562 cells engineered to co-express a CAR activating ligand (CAR-L, a scFV specific to CAR stalk) to sustain proliferation of genetically modified T cells. We validated CAR expression on genetically modified T cells by flow cytometry and western blot. The specificity of HER1-HER3 specific CAR T cells was confirmed in situ by a proximity ligation-based assay using breast cancer cells. The redirected killing by CAR+ T cells to HER1+HER3+ breast cancer cells was confirmed in vitro and its efficacy evaluated in vivo in NSG mice bearing a breast tumor xenograft. HER1-HER3 specific CAR+ T cells activated via CD137 signaling exhibited superior proliferation compared with T cells expressing CAR with CD28 signaling domain. This is consistent with the ability of CD3-zeta/CD137 endodmain to alter mitochondrial metabolism and to suppress apoptosis leading to proliferation after initial activation. In summary, we report a new CAR design that can interrogate the conformation between two tumor-associated antigens (TAAs). This will likely improve specificity and limit on-target off-tissue side effects compared to CARs targeting only HER-1 or HER-3. Thus, targeting an epitope derived from two TAAs may help distinguish normal cells versus malignant cells and treat HER1+HER3+ malignancies that are resistant to therapies targeting single EGFR family members. These data have immediate translation appeal for targeting solid tumors as we use the SB and AaPC platforms to manufacture CAR+ T cells in our clinical trials. Disclosures Cooper: InCellerate: Equity Ownership; Sangamo: Patents & Royalties; Targazyme: Consultancy; GE Healthcare: Consultancy; Ferring Pharmaceuticals: Consultancy; Fate Therapeutics: Consultancy; Janssen Pharma: Consultancy; BMS: Consultancy; Miltenyi: Honoraria.

scholarly journals CD4 T-cell immune stimulation of HER2+ breast cancer cells alters response to trastuzumab in vitro

2020 ◽  
Author(s):  
Patrick Song ◽  
Amer Mansur ◽  
Kari J. Dugger ◽  
Tessa R. Davis ◽  
Grant Howard ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
T Cell ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Receptor Expression ◽  
Immune Stimulation ◽  
Her2 Breast Cancer ◽  
Stimulation Of

Abstract Introduction: The HER2+ tumor immune microenvironment is composed of macrophages, natural killer cells, and tumor infiltrating lymphocytes, which produce pro-inflammatory cytokines. Determining the effect of T-cells on HER2+ cancer cells during therapy could guide immunogenic therapies that trigger antibody-dependent cellular cytotoxicity. This study utilized longitudinal in vitro time-resolved microscopy to measure T-cell influence on trastuzumab in HER2+ breast cancer.Methods: Fluorescently-labeled breast cancer cells (BT474, SKBR3, MDA-MB-453, and MDA-MB-231) were co-cultured with CD4+ T-cells (Jurkat cell line) and longitudinally imaged to quantify cancer cell viability when treated with or without trastuzumab (10, 25, 50 and 100 mg/mL). The presence and timing of T-cell co-culturing was manipulated to determine immune stimulation of trastuzumab-treated HER2+ breast cancer. HER2 and TNF-a expression were evaluated with western blot and ELISA, respectively. Significance was calculated using a two-tailed parametric t-test.Results: The viability of HER2+ cancer cells significantly decreased when exposed to 25 mg/mL trastuzumab and T-cells, compared to cancer cells exposed to trastuzumab without T-cells (p = 0.01). The presence of T-cells significantly increased TNF-a expression in trastuzumab-treated cancer cells (p = 0.02). Conversely, cancer cells treated with TNF-a and trastuzumab had a similar decrease in viability as trastuzumab-treated cancer cells co-cultured with T-cells (p = 0.32).Conclusions: The presence of T-cells significantly increases the efficacy of targeted therapies and suggests trastuzumab may trigger immune mediated cytotoxicity. Increased TNF-a receptor expression suggest cytokines may interact with trastuzumab to create a state of enhanced response to therapy in HER2+ breast cancer, which has potential to reducing tumor burden.

Human Multiple Myeloma and Breast Cancer Cells Evade Immune Rejection Through Expression of Carcinoembryonic Antigen-Related Cell Adhesion Molecule 6.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2942-2942
Author(s):  
Mathias Witzens-Harig ◽  
Dirk Hose ◽  
Simone Jünger ◽  
Christina Pfirschke ◽  
Nisit Khandelwal ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Cell Adhesion Molecule ◽  
Cytotoxic T Cells ◽  
Cd8 T Cell ◽  
Related Cell

Abstract Abstract 2942 Tumor-specific cytotoxic T cells are common in tumor patients, but ineffectively react against autologous tumor cells. Here, we demonstrate in multiple myeloma and breast cancer that human tumor cells escape recognition by tumor-specific CD8+ T cells through carcinoembryonic antigen-related cell adhesion molecule-6 (CEACAM-6) expression. We demonstrate for the first time CEACAM-6 expression in primary and established myeloma and examined the effects of altered CEACAM expression on cytotoxic T cell activity and cytokine secretion against myeloma and breast cancer cells in vitro —, and in vivo, using a xenotransplant mouse model. Cytotoxic T cells from multiple myeloma patients reacted against myeloma antigens presented by dendritic cells, but not against autologous myeloma cells, which expressed CEACAM6. Gene knockdown or blocking of CEACAM6 on myeloma cells restored CD8+ T-cell reactivity against malignant plasma cells. SiRNA-mediated CEACAM6 knockdown or inhibition by specific mAbs also restored cytokine secretion, cytotoxic activity, and antigen-specific lysis of CEACAM6-positive breast cancer cells. Moreover, CEACAM-6 inhibition was a prerequisite for efficient treatment of xenotransplanted breast tumors by adoptive T cell transfer. CEACAM6 thus plays an important role in inhibiting CD8+ T-cell responses against hematological and epithelial human tumors. Therapeutic targeting of CEACAM6 may be a promising strategy for improving cancer immunotherapy. Disclosures: No relevant conflicts of interest to declare.

Abstract 350: Immune Profiling and Causal Antigen Discovery in Mouse and Human Models of Immune Checkpoint Inhibitor-induced Myocarditis

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Han Zhu ◽  
Daniel Lee ◽  
Waliany Sarah ◽  
Francisco X Galdos ◽  
Jessica D’Addabbo ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Myocardial Damage ◽  
T Cell Subsets ◽  
Immune Checkpoints ◽  
Fulminant Myocarditis ◽  
T Cell Infiltration ◽  
Life Threatening

Introduction: Immune checkpoint inhibitors (ICIs) are novel drugs that activate T cell-mediated anti-tumor response by blocking immune checkpoints such as PD-1 or CTLA-4, leading to improved cancer patient survival. Despite these benefits, ICIs can result in autoimmune side effects including fulminant myocarditis and heart failure. While ICI-induced myocarditis is characterized by myocardial T cell infiltration, the causal mechanisms remain unknown. We hypothesize that ICI-induced myocarditis is caused by cardiac-specific auto-antigens triggering clonal expansion of myocardial CD8+ T-cells, leading to T-cell mediated myocardial damage. Methods/Results: We have explored the ICI-induced inflammatory response in a mouse model of myocarditis induced by PD-1 knockout and in patients with ICI-induced myocarditis. PD-1 deficient-mice on a lupus-like autoimmune background (i.e. MRL/Pcd1-/- mice) develop spontaneous fatal myocarditis in 70% of animals by 5 weeks of age, with massive cardiac infiltration of CD8>CD4+ T-cells. Likewise, patients with ICI-induced myocarditis have CD8>CD4+ T-cell infiltrate in the heart. We have performed time-of-flight mass cytometry (CyTOF) to immunophenotype the T-cell subsets in the blood/myocardium of MRL/Pcd1-/- mice and in ICI-myocarditis patients. We have also conducted single cell sequencing of T-cell receptors (TCRs) from the blood +/- myocardial-derived T-cell samples of the mice and patients. Our preliminary results in ICI-myocarditis patients confirmed the previously reported CD8+ T-cell expansion in the blood and myocardium of myocarditis patients compared with healthy control. We are currently identifying candidate cardiac auto-antigen(s) responsible for this disease by performing Grouping Lymphocyte Interactions by Paratope Hotspots (GLIPH). Conclusion: Myocarditis is a serious and life-threatening complication of ICI treatment. By understanding the unique immune response present during ICI-induced myocarditis and the responsible cardiac auto-antigen(s) involved, we will pave the way for the development of adjuvant therapies that target these antigens and mitigate their deleterious effects.

scholarly journals P11.10 The IFNγ pathway mediates brain metastasis formation of breast cancer

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii44-iii44
Author(s):  
R Pedrosa ◽  
J M Kros ◽  
B Schrijver ◽  
R Marques ◽  
P Leenen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Breast Cancer Cells ◽  
T Cell Response ◽  
Activated T Cells

Abstract BACKGROUND In previous work we showed the prominence of the T-cell response in the formation of brain metastases of primary ER negative breast cancers (Mustafa et al, Acta Neuropathol 2018). We also showed that breast cancer cells co-cultured with stimulated T lymphocytes overexpress Guanylate-binding protein 1 (GBP1) accompanying increased trespassing ability through an in vitro blood-brain barrier (BBB) model. In addition, we demonstrated a predilection for metastasizing to brain of breast cancer cells that were co-cultured with activated T cells in a mouse model. We now scrutinize the importance of the IFNγ pathway for tresspassing of the tumor cells through the BBB following T cell contact. MATERIAL AND METHODS Anti-hIFN-γ-IgA antibodies were used to neutralize the IFNγ effects on the tumor cells. The effects on the tumor cells is only due to native IFNγ produced by activated T cells, not by recombinant IFNγ. Since the IFNγ expression itself enhances its expression by the T cells, we blocked IFNγ receptors prior to adding CD3+ T cell conditioned media to the breast cancer cells. The receptor blocking was achieved by antibodies to the IFNγα and IFNγβ subunits. Activation of the STAT1 pathway was monitored by GBP1 expression. For functional read-out the in vitro BBB model was used. RESULTS The presence of T-lymphocyte-secreted IFNγ in the primary breast cancer microenvironment activates the STAT1-dependent IFNγ pathway in breast cancer cells, endowing them with an increased ability to trespass the in vitro BBB. Moreover, direct inhibition of soluble IFNγ, or blocking of the IFNγ-specific receptor in breast cancer cells significantly decreases their ability to cross the BBB. CONCLUSION The results illustrate the specific action of T lymphocytes in the formation of cerebral metastasis involves the IFNγ signaling pathway as one of the crucial entangled pathways Subsequent studies should aim at the interference with the IFNγ pathway to develop preventive strategies against the formation of cerebral metastases of breast cancer.

scholarly journals CD4 T-Cell Immune Stimulation of HER2+ Breast Cancer Cells in Response to Trastuzumab In Vitro

2020 ◽  
Author(s):  
Patrick N. Song ◽  
Amer Mansur ◽  
Kari J. Dugger ◽  
Tessa R. Davis ◽  
Grant Howard ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
T Cell ◽  
Cancer Cells ◽  
Targeted Therapies ◽  
Breast Cancer Cells ◽  
Immune Stimulation ◽  
Her2 Breast Cancer ◽  
Stimulation Of

Abstract Introduction: The HER2+ tumor immune microenvironment is composed of macrophages, natural killer cells, and tumor infiltrating lymphocytes, which produce pro-inflammatory cytokines. Determining the effect of T-cells on HER2+ cancer cells during therapy could guide immunogenic therapies that trigger antibody-dependent cellular cytotoxicity. This study utilized longitudinal in vitro time-resolved microscopy imaging to measure T-cell influence on trastuzumab in HER2+ breast cancer.Methods: Fluorescently-labeled breast cancer cells (BT474, SKBR3, MDA-MB-453, and MDA-MB-231) were co-cultured with CD4+ T-cells (Jurkat cell line) and longitudinally imaged to quantify cancer cell viability when treated with trastuzumab (10, 25, 50 and 100 g/mL). The presence and timing of T-cell co-culturing was manipulated to determine immune stimulation of trastuzumab-treated HER2+ breast cancer. HER2 and TNF- expression were evaluated with western blot and ELISA, respectively. Significance was calculated using a two-tailed parametric t-test.Results: The viability of HER2+ cancer cells significantly decreased when exposed to 25 g/mL trastuzumab and T-cells, compared to cancer cells exposed to trastuzumab without T-cells (p = 0.01). The presence of T-cells significantly increased TNF- expression in trastuzumab-treated cancer cells (p = 0.02). Conversely, cancer cells treated with TNF- and trastuzumab had a similar decrease in viability as trastuzumab-treated cancer cells co-cultured with T-cells (p = 0.49).Conclusions: The presence of T-cells significantly increases the efficacy of targeted therapies and suggests trastuzumab may trigger immune mediated cytotoxicity. TNF- expression suggests cytokines may interact with trastuzumab-induced HER2 receptor blockade. Examining molecular mechanisms of breast cancer immune infiltration has the potential to improve response to targeted therapies.

scholarly journals Traditional Thai Massage Promoted Immunity in the Elderly via Attenuation of Senescent CD4+ T Cell Subsets: A Randomized Crossover Study

2021 ◽  
Vol 18 (6) ◽  
pp. 3210
Author(s):  
Kanda Sornkayasit ◽  
Amonrat Jumnainsong ◽  
Wisitsak Phoksawat ◽  
Wichai Eungpinichpong ◽  
Chanvit Leelayuwat
Keyword(s):  
T Cells ◽  
T Cell ◽  
Crossover Study ◽  
Intracellular Cytokine Staining ◽  
The Elderly ◽  
Complementary Therapy ◽  
T Cell Subsets ◽  
Cd4 T Cell ◽  
T Subsets ◽  
Randomized Crossover Study

The beneficial physiological effects of traditional Thai massage (TTM) have been previously documented. However, its effect on immune status, particularly in the elderly, has not been explored. This study aimed to investigate the effects of multiple rounds of TTM on senescent CD4+ T cell subsets in the elderly. The study recruited 12 volunteers (61–75 years), with senescent CD4+ T cell subsets, who received six weekly 1-h TTM sessions or rest, using a randomized controlled crossover study with a 30-day washout period. Flow cytometry analysis of surface markers and intracellular cytokine staining was performed. TTM could attenuate the senescent CD4+ T cell subsets, especially in CD4+28null NKG2D+ T cells (n = 12; p < 0.001). The participants were allocated into two groups (low < 2.75% or high ≥ 2.75%) depending on the number of CD4+28null NKG2D+ T cells. After receiving TTM over 6 sessions, the cell population of the high group had significantly decreased (p < 0.001), but the low group had no significant changes. In conclusion, multiple rounds of TTM may promote immunity through the attenuation of aberrant CD4+ T subsets. TTM may be provided as a complementary therapy to improve the immune system in elderly populations.

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