scholarly journals Vγ9Vδ2 T Cells Strengthen Cisplatin Inhibition Activity Against Breast Cancer MDA-MB-231 Cells by Destructing Mitochondrial Function and Cell Ultrastructure

2020 ◽  
Author(s):  
Xin Huang ◽  
Cunchuan Wang ◽  
Ningxia Wang
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Cancer Patients ◽  
Mitochondrial Function ◽  
System Development ◽  
Cancer Cell Line ◽  
Chemotherapy Drugs ◽  
Immune System Development ◽  
Vγ9vδ2 T Cells

Abstract Background: Breast cancer ranks second of new cases and fifth of death in 2018 world widely. Chemotherapy, one of cancer therapeutic strategies, plays important role in controlling mortality of breast cancer. Cis-platinum (CDDP), one of traditional chemotherapy drugs, had been used clinically for years. The crucial limitation of CDDP is due to its adverse effects on immune system. Development of new protocol that can minimize side effect and meanwhile elevate clinical efficacy of traditional drug like CDDP will eventually benefit cancer patients. Vγ9Vδ2 T cells had been reported to be able to up-regulate immune function of cancer patients, therefore, our hypothesis is that introduction of Vγ9Vδ2 T cells could potentiate CDDP efficacy against breast cancer. Methods: In the present work, breast cancer cell line MDA-MB-231 was used a model cell to test our hypothesis. The therapeutic dose of CDDP in vitro was analyzed by flow cytometry; The cytoskeleton was visualized by using a confocal microscopy, and the ultrastructure of the membrane was observed by atomic force microscopy to observe the effect of combined action on MDA-MB-231 cells; The mitochondrial function of MDA-MB-231 cells was detected, and the relevant mechanism of Vγ9Vδ2 T in enhancing cisplatin cells' inhibition of MDA-MB-231 cells was discussed. Results: Vγ9Vδ2 T cells could enhance CDDP-induced MDA-MB-231 cell membrane ultrastructure disorder and cytoskeleton disorder, and enhance the inhibition of CDDP on MDA-MB-231 cells, of which Vγ9Vδ2 T cells enhancing CDDP-induced mitochondrial dysfunction was one of its mechanisms. Conclusion: In this study，the mechanism of Vγ9Vδ2 T cells in enhancing the inhibition of cisplatin on MDA-MB-231 cells was studied, which could provide an important scientific clue for developing effective treatment schemes for breast cancer, especially the refractory TNBC breast cancer, based on Vγ9Vδ2 T cells in the future.

scholarly journals Vγ9Vδ2 T cells strengthen cisplatin inhibition activity against breast cancer MDA-MB-231 cells by disrupting mitochondrial function and cell ultrastructure

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Xin Huang ◽  
Cunchuan Wang ◽  
Ningxia Wang
Keyword(s):  
Breast Cancer ◽  
Flow Cytometry ◽  
T Cells ◽  
Cell Membrane ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Mitochondrial Function ◽  
Inhibition Activity ◽  
Vγ9vδ2 T Cells

Abstract Background Breast cancer ranks second of new cases and fifth of death in 2018 worldwide. Cis-platinum (CDDP) has been used as a chemotherapy to treat breast cancer for years. However, CDDP can adversely disrupt immune function of host. Thus, development of new protocol that can minimize side effect and meanwhile elevate clinical efficacy of CDDP will eventually benefit cancer patients. Since Vγ9Vδ2 T cells can up-regulate immune function of cancer patients, therefore, our hypothesis is that introduction of Vγ9Vδ2 T cells could potentiate CDDP efficacy against breast cancer. Methods We used breast cancer cell line MDA-MB-231 as model cell to test our hypothesis. The cancer cell viability in vitro in the context of different dose of CDDP was analyzed by flow cytometry. The cytoskeleton alteration was visualized by confocal microscopy, and the ultrastructure of cell membrane was observed by atomic force microscopy. The mitochondrial function of MDA-MB-231 cells was detected as well by flow cytometry. Results Comparing to either Vγ9Vδ2 T cells or CDDP alone, Vγ9Vδ2 T cells plus CDDP could more strikingly induce MDA-MB-231 cell membrane ultrastructure disruption and cytoskeleton disorder, and more significantly enhance the inhibition of CDDP on proliferation of MDA-MB-231 cells. At the same time, Vγ9Vδ2 T cells strengthened CDDP-induced mitochondrial dysfunction of cancer cells. Conclusion This work revealed that Vγ9Vδ2 T cells could synergistically enhance the inhibition activity of CDDP against breast cancer cells. Meanwhile, this in vitro proof-of-concept study implied the clinical prospect of the combining application of Vγ9Vδ2 T cells and CDDP in breast cancer therapy.

scholarly journals Vγ9Vδ2 T cells strengthen cisplatin inhibition activity against breast cancer MDA-MB-231 cells by disrupting mitochondrial function and cell ultrastructure

2021 ◽  
Author(s):  
Xin Huang ◽  
Cunchuan Wang ◽  
Ningxia Wang
Keyword(s):  
Breast Cancer ◽  
Flow Cytometry ◽  
T Cells ◽  
Cell Membrane ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Mitochondrial Function ◽  
Inhibition Activity ◽  
Vγ9vδ2 T Cells

Abstract Background: Breast cancer ranks second of new cases and fifth of death in 2018 worldwide. Cis-platinum (CDDP) has been used as a chemotherapy to treat breast cancer for years. However, CDDP can adversely disrupt immune function of host. Thus, development of new protocol that can minimize side effect and meanwhile elevate clinical efficacy of CDDP will eventually benefit cancer patients. Since Vg9Vd2 T cells can up-regulate immune function of cancer patients, therefore, our hypothesis is that introduction of Vg9Vd2 T cells could potentiate CDDP efficacy against breast cancer.Methods: We used breast cancer cell line MDA-MB-231 as model cell to test our hypothesis. The cancer cell viability in vitro in the context of different dose of CDDP was analyzed by flow cytometry. The cytoskeleton alteration was visualized by confocal microscopy, and the ultrastructure of cell membrane was observed by atomic force microscopy. The mitochondrial function of MDA-MB-231 cells was detected as well by flow cytometry.Results: Comparing to either Vγ9Vδ2 T cells or CDDP alone, Vg9Vd2 T cells plus CDDP could more strikingly induce MDA-MB-231 cell membrane ultrastructure disruption and cytoskeleton disorder, and more significantly enhance the inhibition of CDDP on proliferation of MDA-MB-231 cells. At the same time, Vγ9Vδ2 T cells strengthened CDDP-induced mitochondrial dysfunction of cancer cells.Conclusion: This work revealed that Vγ9Vδ2 T cells could synergistically enhance the inhibition activity of CDDP against breast cancer cells. Meanwhile, this in vitro proof-of-concept study implied the clinical prospect of the combining application of Vγ9Vδ2 T cells and CDDP in breast cancer therapy.

scholarly journals Immune system development varies according to age, location, and anemia in African children

2020 ◽  
Vol 12 (529) ◽  
pp. eaaw9522 ◽  
Author(s):  
Danika L. Hill ◽  
Edward J. Carr ◽  
Tobias Rutishauser ◽  
Gemma Moncunill ◽  
Joseph J. Campo ◽  
...  
Keyword(s):  
T Cells ◽  
Immune System ◽  
Immune Cell ◽  
System Development ◽  
High Titer ◽  
Geographical Location ◽  
Cell Types ◽  
Iron Bioavailability ◽  
Immune System Development

Children from low- and middle-income countries, where there is a high incidence of infectious disease, have the greatest need for the protection afforded by vaccination, but vaccines often show reduced efficacy in these populations. An improved understanding of how age, infection, nutrition, and genetics influence immune ontogeny and function is key to informing vaccine design for this at-risk population. We sought to identify factors that shape immune development in children under 5 years of age from Tanzania and Mozambique by detailed immunophenotyping of longitudinal blood samples collected during the RTS,S malaria vaccine phase 3 trial. In these cohorts, the composition of the immune system is dynamically transformed during the first years of life, and this was further influenced by geographical location, with some immune cell types showing an altered rate of development in Tanzanian children compared to Dutch children enrolled in the Generation R population–based cohort study. High-titer antibody responses to the RTS,S/AS01E vaccine were associated with an activated immune profile at the time of vaccination, including an increased frequency of antibody-secreting plasmablasts and follicular helper T cells. Anemic children had lower frequencies of recent thymic emigrant T cells, isotype-switched memory B cells, and plasmablasts; modulating iron bioavailability in vitro could recapitulate the B cell defects observed in anemic children. Our findings demonstrate that the composition of the immune system in children varies according to age, geographical location, and anemia status.

scholarly journals Allogeneic Vγ9Vδ2 T-cell immunotherapy exhibits promising clinical safety and prolongs the survival of patients with late-stage lung or liver cancer

2020 ◽  
Author(s):  
Yan Xu ◽  
Zheng Xiang ◽  
Mohammed Alnaggar ◽  
Léonce Kouakanou ◽  
Jiawei Li ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cancer Patients ◽  
Late Stage ◽  
Γδ T Cells ◽  
Humanized Mouse Model ◽  
Clinical Safety ◽  
Lung Cancer Patients ◽  
Vγ9vδ2 T Cells

Abstract Vγ9Vδ2 T cells are promising candidates for cellular tumor immunotherapy. Due to their HLA-independent mode of action, allogeneic Vγ9Vδ2 T cells can be considered for clinical application. To apply allogeneic Vγ9Vδ2 T cells in adoptive immunotherapy, the methodology used to obtain adequate cell numbers with optimal effector function in vitro needs to be optimized, and clinical safety and efficacy also need to be proven. Therefore, we developed a novel formula to improve the expansion of peripheral γδ T cells from healthy donors. Then, we used a humanized mouse model to validate the therapeutic efficacy of expanded γδ T cells in vivo; furthermore, the expanded γδ T cells were adoptively transferred into late-stage liver and lung cancer patients. We found that the expanded cells possessed significantly improved immune effector functions, including proliferation, differentiation, and cancer cell killing, both in vitro and in the humanized mouse model. Furthermore, a phase I clinical trial in 132 late-stage cancer patients with a total of 414 cell infusions unequivocally validated the clinical safety of allogeneic Vγ9Vδ2 T cells. Among these 132 patients, 8 liver cancer patients and 10 lung cancer patients who received ≥5 cell infusions showed greatly prolonged survival, which preliminarily verified the efficacy of allogeneic Vγ9Vδ2 T-cell therapy. Our clinical studies underscore the safety and efficacy of allogeneic Vγ9Vδ2 T-cell immunotherapy, which will inspire further clinical investigations and eventually benefit cancer patients.

scholarly journals IDO Inhibition Facilitates Antitumor Immunity of Vγ9Vδ2 T Cells in Triple-Negative Breast Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Peng Li ◽  
Ruan Wu ◽  
Ke Li ◽  
Wenhui Yuan ◽  
Chuqian Zeng ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Γδ T Cells ◽  
Clinical Samples ◽  
Breast Cancer Patients ◽  
Vγ9vδ2 T Cells

Triple-negative breast cancer (TNBC) escape from immune-mediated destruction was associated with immunosuppressive responses that dampened the activation of tumor-infiltrating CD8 and γδ T cells. TNBC had a higher level of programmed cell death 1-ligand 1 (PD-L1) and indoleamine 2,3-dioxygenase (IDO), compared with other breast cancer subtypes. But, clinical studies have revealed that the response rate of PD-1/PD-L1 antibody for TNBC treatment was relatively low. However, the antitumor responses of human Vγ9Vδ2 T cells or IDO inhibitor in TNBC treatment are unknown. In this study, we found that IDO1 and PD-L1 were highly expressed in TNBC patients. Analysis of the clinical samples demonstrated that Vγ9Vδ2 T cells became exhausted in triple-negative breast cancer patients. And Vγ9Vδ2 T cells combined with αPD-L1 could not further enhance their antitumor responses in vitro and in vivo. However, Vγ9Vδ2 T cells combined with IDO1 inhibitor 1-Methyl-L-tryptophan (1-MT) or Lindrostat showed substantial inhibitory effects on MDA-MB-231 tumor cells. Finally, we found that IDO1 inhibitor promoted T cell’s cytotoxicity by enhancing perforin production. These results converged to suggest the potential application of Vγ9Vδ2 T cells treated with IDO1 inhibitor for TNBC therapy.

scholarly journals PENTOXIFYLLINE ENHANCES IN VITRO T-CELL ANTITUMOR RESPONSE IN BREAST CANCER PATIENTS

2021 ◽  
Vol 23 (4) ◽  
pp. 785-790
Author(s):  
M. S. Kuznetsova ◽  
J. A. Shevchenko ◽  
J. N. Khantakova ◽  
A. A. Khristin ◽  
I. A. Obleukhova ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Metastatic Breast Cancer ◽  
Tumor Growth ◽  
Cancer Patients ◽  
Cell Activity ◽  
Metastatic Breast ◽  
Antitumor Response ◽  
Healthy Donors

The NF-κB transcription factor controls the expression of genes responsible for cell cycle, apoptosis, and other immunoregulatory functions. Some nonspecific NF-κB inhibitors were found after discovering the possibility of blocking tumor growth through suppression of NF-κB activity, but their use was complicated by multiple side effects, such as interleukin-1β-related systemic inflammation or non-immunerelated complications, which may be due to inhibition of the p65 NF-κB subunit that plays a central role in organogenesis and inflammation. Inhibition of the c-Rel subunit leads to tumor growth restriction by modulating the T-regulatory cell activity.In 2017, Grinberg-Bleyer and co-authors checked the hypothesis that selective inhibition of the c-Rel subunit can be performed using pentoxifylline and will effectively regulate Treg activity during tumor growth. The authors showed that pentoxphylline, an FDA-approved drug, could indeed induce selective degradation of c-Rel without affecting p65, and suggested that such an effect could be effective in suppressing tumor growth. In this regard, we aimed to investigate in vitro how pentoxifylline affect the functional activity and antitumor cytotoxic potential of T-cells in cancer patients.The objects of the study were peripheral blood mononuclear cells from 25 patients with primary breast cancer (no metastases), 15 patients with metastatic breast cancer, and 25 healthy women without breast pathology. Informed consent was obtained from all donors and patients. The study was approved by the local ethics committee.Here we showed that pentoxifylline treatment in vitro enhances the pro-apoptotic and cytotoxic antitumor response via increasing the expression of TRAIL on T-lymphocytes, mainly in healthy donors and patients with metastatic breast cancer, both on intact T-cells and in response to the cells of the tumor line of human breast carcinoma ZR-75-1. In healthy donors, in the presence of pentoxifylline, a population of highly expressing TRAIL CD4 and CD8 T-cells appears. 

miR-34a Reverses Doxorubicin Resistance in Breast Cancer

2020 ◽  
Vol 10 (12) ◽  
pp. 1820-1826
Author(s):  
Guolin Ye ◽  
Suqun He ◽  
Ruilin Pan ◽  
Lewei Zhu ◽  
Dan Zhou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Survival Rate ◽  
Cancer Cell Line ◽  
Combination Group ◽  
Tumor Resistance ◽  
Chemotherapy Drugs ◽  
Resistant Strains ◽  
Doxorubicin Group

Chemotherapy is effectively used for treating breast cancer, but the problem of tumor resistance to chemotherapy drugs has been plaguing scientists. Our study investigated miR-34a?s effect on the sensitivity of drug-resistant strains to chemotherapeutic drugs using doxorubicin-resistant strains of breast cancer cells. Cell survival rate was detected by MTT assay. The doxorubicin-resistant strain rMCF-7 was obtained. The cell scratching method and CCK-8 method were used to detect cell migration and proliferation.Western Blot was performed for measuring SIRT1, p-AKT, AKT, p-mTOR and mTOR level. miR-34a significantly reduced the survival rate o doxorubicin-resistant breast cancer cell line rMCF-7 and significantly enhanced doxorubicin?s effect on inhibiting cell proliferation and cell migration. Compared with the doxorubicin group alone, miR-34a and doxorubicin combination group significantly downregulated SIRT1, p-AKT/AKT and p-mTOR/mTOR related proteins in rMCF-7 cells. miR-34a can reverse the resistance of doxorubicin in breast cancer in vitro and the mechanism may be through inhibition of SIRT and AKT signaling.

scholarly journals Autologous Dendritic Cells in Combination With Chemotherapy Restore Responsiveness of T Cells in Breast Cancer Patients: A Single-Arm Phase I/II Trial

2021 ◽  
Vol 12 ◽  
Author(s):  
David A. Bernal-Estévez ◽  
Mauren A. Ortíz Barbosa ◽  
Paola Ortíz-Montero ◽  
Claudia Cifuentes ◽  
Ramiro Sánchez ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Flow Cytometry ◽  
T Cells ◽  
Dendritic Cells ◽  
Adverse Effects ◽  
Phase I ◽  
Cancer Patients ◽  
Functional Performance ◽  
Breast Cancer Patients

IntroductionAnimal studies and preclinical studies in cancer patients suggest that the induction of immunogenic cell death (ICD) by neoadjuvant chemotherapy with doxorubicin and cyclophosphamide (NAC-AC) recovers the functional performance of the immune system. This could favor immunotherapy schemes such as the administration of antigen-free autologous dendritic cells (DCs) in combination with NAC-AC to profit as cryptic vaccine immunogenicity of treated tumors.ObjectiveTo explore the safety and immunogenicity of autologous antigen-free DCs administered to breast cancer patients (BCPs) in combination with NAC-AC.Materials and MethodsA phase I/II cohort clinical trial was performed with 20 BCPs treated with NAC-AC [nine who received DCs and 11 who did not (control group)]. The occurrence of adverse effects and the functional performance of lymphocytes from BCPs before and after four cycles of NAC-AC receiving DCs or not were assessed using flow cytometry and compared with that from healthy donors (HDs). Flow cytometry analysis using manual and automated algorithms led us to examine functional performance and frequency of different lymphocyte compartments in response to a stimulus in vitro. This study was registered at clinicaltrials.gov (NCT03450044).ResultsNo grade II or higher adverse effects were observed associated with the transfer of DCs to patients during NAC-AC. Interestingly, in response to the in vitro stimulation, deficient phosphorylation of Zap70 and AKT proteins observed before chemotherapy in most patients’ CD4 T cells significantly recovered after NAC-AC only in patients who received DCs.ConclusionsThe transfer of autologous DCs in combination with NAC-AC in BCPs is a safe procedure. That, in BCPs, the administration of DCs in combination with NAC-AC favors the recovery of the functional capacity of T cells suggests that this combination may potentiate the adjuvant effect of ICD induced by NAC-AC on T cells and, hence, potentiate the immunogenicity of tumors as cryptic vaccines.

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