Association between γδ T cells and clinicopathological features of breast cancer

Abstract Background: The precancerous disease of breast cancer is an inevitable stage in the emergence and development of breast neoplasms. Breast cancer (BC) is a common malignant tumor in female worldwide. A large number of literatures have proved that, as antitumor drugs, flavonoid compounds can promote proliferation and immune regulation of T cell. Many researchers believe that Quercetin (Que) has great potential in the field of anti-breast cancer. Besides that, γδ T cells are a class of non-traditional T cells, which have long attracted attention due to their potential in immunotherapy. Above all, JAK/STAT1 signaling pathway is closely related to the immunity.MethodsIn the experiment designed in this paper, we first used Que, one of the flavonoids, to screen the target gene. Then, MCF-10A, MCF-10AT, MCF-7 and MDA-MB231 BC cells were co-cultured with Que for 24h and 48h, apoptosis was found in some the cells. We then cultured Que with γδ T cells and found that Que can promote the proliferation of Vδ2 T cell subsets of γδ T cells, thus enhancing the killing effect of γδ T cells. Western blot was use to showed the change of JAK/STAT1 signaling pathway related proteins after the Que was co-cultured with MCF-10AT and MCF-7 for 48h.ResultsNetwork pharmacology has shown that Que related pathways include the JAK/STAT1 signaling pathway and are associated with precancerous breast cancers. Que induced apoptosis of MCF-10AT, MCF-7 and MDA-MB-231 in a time and concentration-dependent manner. Most importantly, Que can promote the differentiation of γδ T cells into the Vδ2 T cell subpopulation, this means that Que and γδ T cells may play a synergistic role in killing tumor cells and cellular immune regulation. In addition, our results showed that Que can increase in protein levels of IFNγ-R, p-JAK2 and p-STAT1, while the concomitant decrease protein levels of PD-L1.ConclusionsIn conclusion, Que plays a synergistic role in killing BC cells and promoting apoptosis by regulating the expression of IFNγ-R, p-JAK2, p-STAT1, and PD-L1 in the JAK/STAT1 signaling pathway and promoting the regulation of γδ T cells. Que may be a potential drug for the prevention of precancerous breast cancer and adjuvant treatment of BC.

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γδ T cells Promote Breast Cancer Metastasis via Regulation of Neutrophils

Cancer Discovery ◽

10.1158/2159-8290.cd-rw2015-065 ◽

2015 ◽

Vol 5 (5) ◽

pp. 463.1-463

Keyword(s):

Breast Cancer ◽

T Cells ◽

Cancer Metastasis ◽

Γδ T Cells ◽

Breast Cancer Metastasis ◽

Promote Breast Cancer

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An innate-like Vδ1+ γδ T cell compartment in the human breast is associated with remission in triple-negative breast cancer

Science Translational Medicine ◽

10.1126/scitranslmed.aax9364 ◽

2019 ◽

Vol 11 (513) ◽

pp. eaax9364 ◽

Cited By ~ 23

Author(s):

Yin Wu ◽

Fernanda Kyle-Cezar ◽

Richard T. Woolf ◽

Cristina Naceur-Lombardelli ◽

Julie Owen ◽

...

Keyword(s):

Breast Cancer ◽

T Cells ◽

T Cell ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Γδ T Cells ◽

Γδ T Cell ◽

Human Breast ◽

Cell Compartment ◽

Αβ T Cells

Innate-like tissue-resident γδ T cell compartments capable of protecting against carcinogenesis are well established in mice. Conversely, the degree to which they exist in humans, their potential properties, and their contributions to host benefit are mostly unresolved. Here, we demonstrate that healthy human breast harbors a distinct γδ T cell compartment, primarily expressing T cell receptor (TCR) Vδ1 chains, by comparison to Vδ2 chains that predominate in peripheral blood. Breast-resident Vδ1+ cells were functionally skewed toward cytolysis and IFN-γ production, but not IL-17, which has been linked with inflammatory pathologies. Breast-resident Vδ1+ cells could be activated innately via the NKG2D receptor, whereas neighboring CD8+ αβ T cells required TCR signaling. A comparable population of Vδ1+ cells was found in human breast tumors, and when paired tumor and nonmalignant samples from 11 patients with triple-negative breast cancer were analyzed, progression-free and overall survival correlated with Vδ1+ cell representation, but not with either total γδ T cells or Vδ2+ T cells. As expected, progression-free survival also correlated with αβ TCRs. However, whereas in most cases TCRαβ repertoires focused, typical of antigen-specific responses, this was not observed for Vδ1+ cells, consistent with their innate-like responsiveness. Thus, maximal patient benefit may accrue from the collaboration of innate-like responses mounted by tissue-resident Vδ1+ compartments and adaptive responses mounted by αβ T cells.

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Defective γδ T-Cell Function and Granzyme B Gene Polymorphism in Newly Diagnosed Breast Care Patients. Expansion with Zoledronic Acid Partially Compensates for This Deficiency.

Blood ◽

10.1182/blood.v108.11.3880.3880 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3880-3880

Author(s):

Ameera Gaafar ◽

Abdulla Al-Sulaiman ◽

Alia Iqniebi ◽

Adher Al-Sayed ◽

Entezam Sahovic ◽

...

Keyword(s):

Breast Cancer ◽

T Cells ◽

Zoledronic Acid ◽

Gene Polymorphism ◽

Cancer Patients ◽

Granzyme B ◽

Γδ T Cells ◽

Breast Cancer Patients ◽

Ifn Γ ◽

Normal Controls

Abstract It has been well established that γδ T-cells play a role in innate anti-tumor immunity. However, the exact mechanism has not yet been fully elucidated. Most of these responses have been ascribed to Vγ9Vδ2 cells, which represent a major subset of the circulating γδ T-cells in humans (1–10%). IFN-γ and granzyme B are important molecules in the anti-tumor immune responses. Upon stimulation, γδ T-cells rapidly produce IFN-γ and cytotoxic molecules. In the present study we analyzed the immune responses by γδ T-cells in 30 newly diagnosed breast cancer patients and 30 normal controls before and after expansion with zoledronic acid. We also scanned the granzyme B gene polymorphism in breast cancer patients and controls. Our result revealed that γδ-T cells in PBMC were reduced in both frequency and function in breast cancer patients compared with the normal controls. Ex-vivo stimulation of γδ T-cells with zoledronic acid and IL-2 partially compensated for this deficiency, as it stimulates production of IFN- γ and release of cytotoxic molecules by these cells. However, the IFN- γ and granzyme B and cytotoxicity of the expanded γδ T-cells from breast cancer patients remained significantly below normal control. Genotypic analysis of granzyme B gene revealed significantly higher frequency of the RAH haplotype in breast cancer patients compared with normal controls. The prevalence of the wild genotype QPY/QPY was significantly higher in normal controls compared with the breast cancer patients. Cytotoxicity by γδ T-cells against various targets was reduced in breast cancer patients compared to normal controls. In conclusion, our analysis shows a defective immune function of γδ T-cells and granzyme B gene polymorphism in breast cancer patients. The γδ T-cell function defect in these patients can be partially corrected by zoledronic acid. Further studies of γδ T-cell function and granzyme B gene polymorphism in other cancers, as well as the therapeutic use of zoldedronic acid is warranted.

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Activation by zoledoronic acid and IL-18 of γδ T cells from early-stage breast cancer patients in the context of helper NK cells.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e21004 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e21004-e21004

Author(s):

Tomoharu Sugie ◽

Kaoru Murata-Hirai ◽

Masashi Iwasaki ◽

Craig T Morita ◽

Wen Li ◽

...

Keyword(s):

Breast Cancer ◽

T Cells ◽

Nk Cells ◽

Cancer Patients ◽

Ex Vivo ◽

Early Stage ◽

Γδ T Cells ◽

Early Stage Breast Cancer ◽

Breast Cancer Patients ◽

Vγ2vδ2 T Cells

e21004 Background: Human γδ T cells display potent cytotoxicity against various tumor cells pretreated with zoledronic acid (Zol). Zol has shown benefits when added to adjuvant endocrine therapy for patients with early-stage breast cancer or to standard chemotherapy for patients with multiple myeloma. Although γδ T cells may contribute to this additive effect, the responsiveness of γδ T cells from early-stage breast cancer patients has not been fully investigated. In this study, we determined the number, frequency, and responsiveness of Vγ2Vδ2 T cells from early- and late-stage breast cancer patients and examined the effect of IL-18 on their ex vivo expansion. Methods: Breast cancer patients (n=80) were enrolled after institutional review board approval and with written informed consent. Peripheral blood mononuclear cells (PBMC) were purified and stimulated with Zol/IL-2 or Zol/IL-2/IL-18 for 2 to 10 days. The expanded cells were assessed on flow cytometry and the production of IFN-γ and TNF-α measured through ELISA. Results: The responsiveness of Vγ2Vδ2 T cells from patients with low frequencies of Vγ2Vδ2 T cells was significantly diminished. IL-18, however, enhanced ex vivo proliferative responses of Vγ2Vδ2T cells and helper NK cells (CD3-CD56brightCD11c+CD14-CD16+NKGD2+NKp44low) from patients with either low or high frequencies of Vγ2Vδ2 T cells. Cell-to-cell contact between γδ T and helper NK cells appeared to promote expansion of γδ T cells. Exogenous IL-18 markedly enhanced IFN-γ and TNF-α production from PBMC stimulated by Zol/IL-2, whereas the addition of an anti-IL-18Rα mAb reduced cytokine production. Conclusions: These results demonstrate that Zol elicits immunological responses by γδ T cells from early-stage breast cancer patients and IL-18 enhances proliferative responses and effector functions of γδ T cells in the context of helper NK cells.

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γδ T Cells Predict Outcome in Zoledronate‐Treated Breast Cancer Patients

The Oncologist ◽

10.1634/theoncologist.2013-0097 ◽

2013 ◽

Vol 18 (8) ◽

Cited By ~ 5

Author(s):

Joanne L. Welton ◽

Salvador Martí ◽

Mohammed H. Mahdi ◽

Clare Boobier ◽

Peter J. Barrett‐Lee ◽

...

Keyword(s):

Breast Cancer ◽

T Cells ◽

Cancer Patients ◽

Γδ T Cells ◽

Breast Cancer Patients ◽

Treated Breast ◽

Treated Breast Cancer

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Adoptively transferred ex vivo expanded γδ-T cells mediate in vivo antitumor activity in preclinical mouse models of breast cancer

Breast Cancer Research and Treatment ◽

10.1007/s10549-009-0527-6 ◽

2009 ◽

Vol 122 (1) ◽

pp. 135-144 ◽

Cited By ~ 39

Author(s):

Benjamin H. Beck ◽

Hyung-Gyoon Kim ◽

Hyunki Kim ◽

Sharon Samuel ◽

Zhiyong Liu ◽

...

Keyword(s):

Breast Cancer ◽

T Cells ◽

Antitumor Activity ◽

Mouse Models ◽

Ex Vivo ◽

Γδ T Cells ◽

In Vivo Antitumor Activity

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To explore immune synergistic function of Quercetin in inhibiting breast cancer cells

Cancer Cell International ◽

10.1186/s12935-021-02345-5 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Dan Qiu ◽

Xianxin Yan ◽

Xinqin Xiao ◽

Guijuan Zhang ◽

Yanqiu Wang ◽

...

Keyword(s):

Breast Cancer ◽

T Cells ◽

Cancer Cells ◽

Signaling Pathway ◽

Breast Cancer Cells ◽

Γδ T Cells ◽

Killing Effect ◽

Protein Levels ◽

Stat1 Signaling ◽

Mcf 7

Abstract Background The precancerous disease of breast cancer is an inevitable stage in the tumorigenesis and development of breast neoplasms. Quercetin (Que) has shown great potential in breast cancer treatment by inhibiting cell proliferation and regulating T cell function. γδ T cells are a class of nontraditional T cells that have long attracted attention due to their potential in immunotherapy. In this study, we revealed the immunomodulatory function of Que through regulation of the JAK/STAT1 signaling pathway, which was followed by the synergistic killing of breast cancer cells. Methods In the experimental design, we first screened target genes with or without Que treatment, and we intersected the Que target with the disease target by functional enrichment analysis. Second, MCF-10A, MCF-10AT, MCF-7 and MDA-MB-231 breast cancer cell lines were treated with Que for 0 h, 24 h and 48 h. Then, we observed the expression of its subsets by coculturing Que and γδ T cells and coculturing Que and γδ T cells with breast tumor cells to investigate their synergistic killing effect on tumor cells. Finally, Western blotting was used to reveal the changes in proteins related to the JAK/STAT1 signaling pathway after Que treatment in MCF-10AT and MCF-7 cells for 48 h. Results The pathway affected by Que treatment was the JAK/STAT1 signaling pathway and was associated with precancerous breast cancer, as shown by network pharmacology analysis. Que induced apoptosis of MCF-10AT, MCF-7 and MDA-MB-231 cells in a time- and concentration-dependent manner (P < 0.05). Most importantly, Que promoted the differentiation of γδ T cells into the Vδ2 T cell subpopulation. The best ratio of effector cells to target cells (E/T) was 10:1, the killing percentages of γδ T cells against MCF-10A, MCF-10AT, MCF-7, and MDA-MB-231 were 61.44 ± 4.70, 55.52 ± 3.10, 53.94 ± 2.74, and 53.28 ± 1.73 (P = 0.114, P = 0.486, and P = 0.343, respectively), and the strongest killing effect on precancerous breast cancer cells and breast cancer cells was found when the Que concentration was 5 μM and the E/T ratio was 10:1 (64.94 ± 3.61, 64.96 ± 5.45, 55.59 ± 5.98, and 59.04 ± 5.67, respectively). In addition, our results showed that Que increased the protein levels of IFNγ-R, p-JAK2 and p-STAT1 while decreasing the protein levels of PD-L1 (P < 0.0001). Conclusions In conclusion, Que plays a synergistic role in killing breast cancer cells and promoting apoptosis by regulating the expression of IFNγ-R, p-JAK2, p-STAT1 and PD-L1 in the JAK/STAT1 signaling pathway and promoting the regulation of γδ T cells. Que may be a potential drug for the prevention of precancerous breast cancer and adjuvant treatment of breast cancer.

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