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Simultaneous Evaluation of Regulatory Molecules CXC Chemokine Receptor 3 (CXCR3), Programmed Cell Death Protein 1 (PD-1), Natural Killer Group 2 Member D (NKG2D), and Transforming Growth Factor Beta Receptor II (TGF-βRII) on T Lymphocytes of Newly Diagnosed Breast Cancer Patients
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Elaheh Arianfar1    , Ghazaleh Alizad2 , Ali Memarian *3 |
1- M.Sc in Immunology, Department of Immunology, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran.
2- Golestan Research Center of Gastroenterology and Hepatology (GRCGH), Golestan University of Medical Sciences, Gorgan, Iran.
3- Associate Professor, Department of Immunology, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran. , alimemarian@goums.ac.ir |
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Keywords: Breast Neoplasms [MeSH], T-Lymphocytes [MeSH], Receptors, CXCR3 [MeSH], Programmed Cell Death 1 Receptor [MeSH], NK Cell Lectin-Like Receptor Subfamily K [MeSH], Receptors, Transforming Growth Factor beta [MeSH], Interferon-gamma [MeSH], MHC class I-related chain A [MeSH]
Article ID: Vol27-23 |
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Type of Study: Original Articles |
Subject:
Immunology
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Abstract: (18 Views) |
Extended Abstract
Introduction
Breast cancer is considered one of the most prevalent diseases globally. Female gender, mutations in the BRCA1 and BRCA2 genes, family history, alcohol consumption, obesity, age of first pregnancy older than 35 years, early menarche, late menopause, and nulliparity or late-age pregnancy are among the risk factors identified for this disease.
Since immune responses can play a key role in inhibiting the onset and progression of this disease, a precise understanding of the regulatory features of the immune system is of paramount importance. Cancer immunotherapy enhances the power of immune system responses against the tumor, either actively or passively. The goal of passive immunotherapy is to strengthen the body's existing anti-tumor responses, and it involves the use of monoclonal antibodies, lymphocytes, and cytokines. Active immunotherapy redirects the immune system to attack cancer cells by targeting antigens expressed on their surface. The types of cells used in this approach include natural killer (NK) cells, cytotoxic T lymphocytes (CTLs), and dendritic cells. Activating and recruiting immune system cells, particularly lymphocytes and NK cells, to the tumor microenvironment is one of the main therapeutic mechanisms for breast cancer.
T lymphocytes play a vital role in both the cell-mediated and humoral components of immunity. Studies have indicated that the suppression and dysfunction of these cells are associated with a high risk of developing cancer.
NK group 2 member D (NKG2D) is a type 2 transmembrane protein expressed on NK cells, CD8+ T cells, CD4+ T cells, and Tαβ cells. NKG2D recognizes a large family of stress ligands, including major histocompatibility complex class I chain related gene-A (MICA), MICB, and the UL16-binding protein (ULBP) family (ULBP1-6), which are expressed on human tumor cells. Through interaction with these ligands, NKG2D regulates tumor cell death. Studies have demonstrated that tumor formation can be inhibited through NKG2D signaling. Furthermore, the expression of an NKG2D ligand is sufficient to induce cytolysis by an NKG2D-expressing effector cell. NKG2D-mediated killing in CD8+ T cells requires the simultaneous activation of the T-cell receptor (TCR). Additionally, the co-activation of NKG2D with the TCR in CD4+T cells leads to proliferation and the production of the cytokines interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α).
Transforming growth factor beta (TGF-β) is recognized as a critical immunosuppressive factor within the tumor microenvironment. It facilitates angiogenesis, suppresses IFN-γ secretion by T cells, impairs the maturation of helper T cells, reduces NKG2D expression, and consequently diminishes T cell cytotoxic activity, thereby promoting tumor progression.
Among the three isoforms of the large mammalian TGF-β family, TGF-β1 exhibits the greatest increase in tumor cells. Following the binding of TGF-β to TGF-β receptor II (TGF-βRII), two TGF-βRII molecules and two TGF-β receptor I (TGF-βRI) molecules form a heterotetramer. The TGF-βRII then leads to the phosphorylation of TGF-βRI, which ultimately results in the regulation of the corresponding transcription factors. Therefore, TGF-βRII is examined as the key molecule in assessing the presence of this receptor.
Increased presence and performance of T lymphocytes are necessary characteristics for assessing cancer prognosis. In tumor environments, high titers of both type I and type II IFNs (IFN-I and IFN-II) induce the secretion of the chemokines CXC motif chemokine ligand 9 (CXCL9), CXCL10, and CXCL11. These ligands are potent chemokines for recruiting CXC chemokine receptor 3 (CXCR3) + NK or CXCR3+ T cells toward solid tumors, enabling them to migrate to inflammatory sites, proliferate, and participate in cancer immunosurveillance. Several studies suggest a relationship between CXCR3 expression and breast, colon, renal, and prostate cancers in humans. Conversely, CXCR3 is also expressed on various types of regulatory T (Treg) cells (CD4+ Treg and CD8+ Treg). The expression of CXCR3 on these Treg subsets plays a critical role in their recirculation and recruitment to different inflammatory sites.
Programmed cell death protein 1 PD-1 (CD279) is an immune checkpoint receptor variably expressed on various cell types in the body, including T cells, Tregs, exhausted T cells, NK cells, and NK T (NKT) cells. PD-1 is expressed at low levels on the surface of resting T cells, whereas its expression is increased on the surface of activated T cells.
PD-1 expression is upregulated on T lymphocytes due to persistent activation of these cells, and its resultant interactions lead to the inhibition of T cell activation, proliferation, and cytokine production, ultimately resulting in T lymphocyte exhaustion. Furthermore, PD-1 blockade has been associated with the control of certain cytokine production, including a reduction in vascular endothelial growth factor (VEGF), thereby correlating with anti-tumor immunity and reduced angiogenesis. Given the critical role of T lymphocytes in identifying and preventing the spread of breast cancer tumor cells, this study was conducted to simultaneously evaluate the regulatory molecules CXCR3, PD-1, NKG2D, and TGF-βRII on T lymphocytes of newly diagnosed breast cancer patients.
Methods
This case-control study was conducted on 26 newly diagnosed breast cancer patients admitted to the Fifth Azar Educational-Therapeutic Center in Gorgan, Iran, and 12 non-breast cancer individuals.
First, 10 mL of peripheral blood was collected from all participants into a heparinized tube. The plasma from all samples was separated and stored at −70℃ for subsequent enzyme-linked immunosorbent assay (ELISA) testing. After isolation using a Ficoll solution and density gradient, the peripheral blood mononuclear cells (PBMCs) were prepared for flow cytometry analysis. The populations of T lymphocytes (FITC anti-human CD56 antibody) and NK cells were determined in samples from all patients and control subjects using monoclonal antibodies conjugated with fluorescent materials from Biolegend (APC anti-human CD3 antibody). Subsequently, the expression frequency percentages of the markers NKG2D, PD-1, CXCR3, and TGF-βRII within the aforementioned cell populations were investigated using the following antibodies: PerCP/Cyanine5.5 anti-human CXCR3 antibody; PE anti-human PD-1 antibody; PerCP/Cyanine5.5, anti-human NKG2D antibody; and TGF-βRII phycoerythrin (PE)-conjugated antibody.
The samples were read and analyzed using a flow cytometer (BD Accuri C6). To perform the ELISA test, following the protocol suggested by the kit manufacturers, Biolegend (for IFN-γ) and R&D (for MIC-A), stored plasma samples at -70℃ were utilized to measure the concentration levels of IFN-γ and
MIC-A.
Results
In the flow cytometric four-color analysis of the CD3+CD56- population (T cells), the percentage frequency of these cells in the peripheral blood of patients was significantly lower than in the control group (P<0.001). Furthermore, the percentage of TGF-βRII and PD-1 expression in the peripheral blood of patients (P<0.019) showed a statistically significant increase compared to the control group (P<0.011). Conversely, the percentage of NKG2D and CXCR3 expression in patients was significantly lower than in the control group (P<0.001).
The results of IFN-γ and MIC-A concentrations in the peripheral blood of newly diagnosed breast cancer patients demonstrated a statistically significant increase in MIC-A compared to the control group (P<0.001). In contrast, no statistically significant difference was found in IFN-γ concentrations between the case and control groups.
No statistically significant difference was found between all the variables examined, including CXCR3, PD-1, NKG2D, and TGF-βRII, and the pathological and laboratory features of the case and control groups.
A significant positive correlation was found between the percentage of TGF-βRII expression (in the CD3+CD56+ cell population) and the plasma concentration of MIC-A in patients (r=0.612, P=0.034). Furthermore, a significant inverse correlation was observed between the percentage of PD-1 expression on these cells and the plasma concentration of IFN-γ in the control group (r=−0.787, P=0.012).
Conclusion
Based on the results of the present study, T cells in newly diagnosed breast cancer patients exhibited a suppressed phenotype, accompanied by increased expression of inhibitory markers and decreased expression of activating markers.
In the current study, this reduction in the frequency of T lymphocytes in the case group compared to the control group may indicate the negative effect of the tumor microenvironment on the number and differentiation of T lymphocytes in breast cancer patients and on disease progression.
Differences in the expression of target molecules were observed in T-cell populations in the results of this study, which could provide a justification for the reduced cytotoxic activity of these cells and the progression and evolution of tumors in breast cancer patients.
Tumor formation can be inhibited through NKG2D signaling (ITAM and DAP10-dependent) and by the release of cytotoxicity-associated molecules, namely IFN-γ and TNF-α. Experimental and clinical evidence has demonstrated that reduced expression of the NKG2D receptor is associated with decreased T lymphocyte cytotoxicity and increased formation of aggressive tumors.
Our findings reveal a reduction in the expression of the NKG2D receptor on T lymphocytes in the peripheral blood of patients, as well as an increase in the serum level of MIC-A in breast cancer patients compared to the control group, which may be associated with a decrease in the cytotoxic activity of NK cells.
Proteolytic shedding of NKG2D ligands not only reduces their expression on the surface of tumor cells but also results in secreted MIC-A binding to NKG2D, leading to its internalization and lysosomal degradation on the surface of NK and CD8+ T cells. Furthermore, it is also plausible that factors present in the tumor microenvironment, such as TGF-β, which are secreted by tumor cells and CD4+ CD25+ Treg cells, can culminate in a decrease in NKG2D expression on the surface of T cells and a reduction of its ligands on the surface of tumor cells.
In the present study, an increase in the expression of TGF-βRII on the surface of peripheral blood T lymphocytes was observed in breast cancer patients compared to normal individuals. Considering that reduced expression of TGF-βRII on the surface of cancer cells leads to increased cellular resistance to the growth-inhibitory effects of TGF-β, tumor progression, and angiogenesis, it is thus expected that on the surface of immune cells, such as T cells, an increase in TGF-βRII expression would be observed, consequently leading to decreased resistance to TGF-β growth inhibition and subsequent suppression of the immune system in the context of tumor progression. Since MIC-A levels are elevated as a marker of disease progression in cancer patients, the existence of a direct correlation between the inhibitory marker TGF-βRII and the concentration of MIC-A secreted in the patients' serum in our study may indicate that patients with immunosuppression exhibit greater and more robust progression. These patients express higher levels of the inhibitory TGF-βRII receptors on the surface of their T cells, which could be associated with the negative effect of TGF-β signaling via TGF-βRII and the resulting T lymphocyte immunosuppression in the peripheral blood of breast cancer patients.
Ethical Statement
This article was approved by the Research Ethics Committee of Golestan University of Medical Sciences (IR.GOUMS.REC.1398.020).
Funding
This article has been extracted from the master's thesis of Ms. Elaheh Arianfar in Medical Immunology at the School of Medicine, Golestan University of Medical Sciences. It is also part of a research project (No. 110632) approved by the Gastroenterology and Hepatology Research Center, Golestan University of Medical Sciences. The study was funded by the Vice-Chancellor of Research and Technology, Golestan University of Medical Sciences.
Conflicts of Interest
No conflict of interest.
Acknowledgments
We would like to thank the Gastroenterology and Hepatology Research Center, Golestan University of Medical Sciences, for their financial support. We also sincerely thank Dr. Seyed Reza Khandoozi, a Radiation Oncologist, for his cooperation in executing the project and collecting the samples.
Authors' Contributions
Elaheh Arianfar (M.Sc): Project execution, Data collection, Data analysis, Interpretation of the results, Drafting of the initial manuscript, Approval of the final manuscript.
Ghazaleh Alizad (M.Sc): Project execution, Data analysis, Drafting of the initial manuscript, Approval of the final manuscript.
Ali Memarian (Ph.D): Project administration and design, Data analysis, Interpretation of the results, Approval of the final manuscript.
Key Message: Increased expression of TGF-βRII and PD-1 alongside decreased expression of NKG2D and CXCR3, as well as reduced MIC-A levels in newly diagnosed breast cancer patients, may be associated with the upregulation and potent suppression of T lymphocyte immunity and their dysfunction in breast cancer disease.
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Arianfar E, Alizad G, Memarian A. Simultaneous Evaluation of Regulatory Molecules CXC Chemokine Receptor 3 (CXCR3), Programmed Cell Death Protein 1 (PD-1), Natural Killer Group 2 Member D (NKG2D), and Transforming Growth Factor Beta Receptor II (TGF-βRII) on T Lymphocytes of Newly Diagnosed Breast Cancer Patients. J Gorgan Univ Med Sci 2025; 27 (3) :21-31 URL: http://goums.ac.ir/journal/article-1-4546-en.html
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