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Simple Summary: New insights into the foundation of cellular and molecular cancer immunology have revealed that immune cells play crucial roles in the development and growth of breast cancer (BC). T-cells are one of the most important cells in the tumor microenvironment and are divided into several subtypes including helper, cytotoxic, and regulatory subsets according to their transcription factors, markers, and functions. This article provides a comprehensive review of contradictory functions of various T-cell subsets in the prognosis and treatment of patients with BC, and crosstalk between tumor cells and T-cells. The literature shows that the role of T-cells in BC immunity depends on a variety of factors, including the tumor type or subtype, the stage of the disease, the localization of the cells in the tumor tissue and the presence of different cells or cytokines. Breast cancer (BC) is the most common cancer type in women and the second leading cause of death. Despite recent advances, the mortality rate of BC is still high, highlighting a need to develop new treatment strategies including the modulation of the immune system and immunotherapies. In this regard, understanding the complex function of the involved immune cells and their crosstalk with tumor cells is of great importance. T-cells are recognized as the most important cells in the tumor microenvironment and are divided into several subtypes including helper, cytotoxic, and regulatory T-cells according to their transcription factors, markers, and functions. This article attempts to provide a comprehensive review of the role of T-cell subsets in the prognosis and treatment of patients with BC, and crosstalk between tumor cells and T-cells. The literature overwhelmingly contains controversial findings mainly due to the plasticity of T-cell subsets within the inflammatory conditions and the use of different panels for their phenotyping. However, investigating the role of T-cells in BC immunity depends on a variety of factors including tumor types or subtypes, the stage of the disease, the localization of the cells in the tumor tissue and the presence of different cells or cytokines. [ABSTRACT FROM AUTHOR]

Introduction: The frequencies and functions of T stem cell memory (TSCM) subsets vary in autoimmune diseases. We evaluated the frequencies of CD4+ and CD8+ TSCM subsets as well as their PD‐1 expression levels in patients with T1D. Methods: Blood samples were collected from new case (NC) (n = 15), and long‐term (LT) (n = 15) groups and healthy controls (n = 15). Five subsets of T cells including TCM(CD4+/CD8+ CCR7+ CD45RO+ CD95+), TCMhi (CD4+/CD8+ CCR7+ CD45ROhi CD95+), TEM(CD4+/CD8+ CCR7− CD45RO+ CD95+), TSCM(CD4+/CD8+ CCR7+ CD45RO− CD95+), and T naive (CD4+/CD8+ CCR7+ CD45RO− CD95−) were detected by flow‐cytometry. Results: The frequency of CD4+ TSCM was higher in NC patients than LT patients and controls (p <.0001 and p =.0086, respectively). A higher percentage of the CD8+ T naive cells was shown in NC patients as compared with LT and healthy individuals (p =.0003 and p =.0002, respectively). An increased level of PD‐1 expression was observed on the CD4+TCM and TCMhi cells in LT patients as compared with healthy controls (p =.0037 and p =.0145, respectively). Also, the higher PD‐1 expression was observed on the CD8+ TCM and TCMhi in NC and LT patients as compared with controls (p =.0068 and p <.0001; p =.0012 and p =.0012, respectively). Conclusion: Considering TSCMs' capacities to generate all memory and effector T cells, our results may suggest a potential association between the increased frequencies of TSCMs and T1D progression. [ABSTRACT FROM AUTHOR]

In addition to generating effective immunity against infectious agents, the immune system helps to fight against different noninfectious human diseases while maintaining the balance between self and non-self discrimination. The breakdown of tolerance in autoimmune diseases or sustainable tolerance in an abnormal microenvironment such as chronic inflammation may initiate the process of malignancy. Immune system regulation is controlled by a complex, dynamic network of cells and mediators. Understanding the cellular and molecular basis of immune regulation provides better insight into the mechanisms governing the immune pathology of diseases. Among several cellular subsets and mediators with regulatory roles, a subpopulation of CD4+ T cells was recently reported to be positive for FoxP3 and negative for CD25, with a suggested range of functional activities in both cancer and autoimmune diseases. This CD4 subset was first reported in 2006 and thought to have a role in the pathogenesis of cancer. However, the spectrum of roles played by this T cell subset is broad, and no consensus has been reached regarding its immunological functions. In this review, we focused on the possible origin of CD4+CD25‒FoxP3+ T cells and their function in cancer and autoimmune diseases. [ABSTRACT FROM AUTHOR]

Background: Human immunological memory is a hallmark of the adaptive immune system and plays an important role in the development of effective immune responses against tumors. In the present study, we aimed to determine the frequencies of CD8+ memory T cell subsets including T stem cell memory (TSCM) in tumor-draining lymph nodes of patients with breast cancer (BC).Methods: Mononuclear cells were obtained from axillary lymph nodes of 52 untreated patients with BC and stained for CD8, CCR7, CD45RO, CD95 markers to detect different subtypes of memory cells in the CD8+ lymphocyte population. Data were acquired on four-color flow cytometer and analyzed with CellQuest Pro software.Results: We observed that 47.65 ± 2.66% of CD8+ lymphocytes expressed the CD45RO, a marker for memory T cells. Statistical analysis showed that the total frequency of central memory T cells (TCM) and their subset with low CD45RO expression was significantly higher in tumor-involved nodes compared to tumor-free ones (P = 0.024 and P = 0.017, respectively). The level of CD95 expression (based on mean fluorescence intensity) on the surface of TCM, their CD45ROhi and CD45ROlow subsets, and TSCM was higher in patients with stage II compared to those in stage I (P < 0.05). In addition, the percentage of naive CD8+ T cells was significantly lower in tumor-involved lymph nodes compared to tumor-free ones (P = 0.025).Conclusions: Our data collectively indicate no significant differences in the frequencies of CD8+ lymphocytes or their memory subsets in tumor-draining lymph nodes of patients with BC. However, the frequency of CD45low TCM was higher in tumor-involved nodes. Along with a decrease in the frequency of naive T cells, the higher frequency of CD45low TCM suggests that despite the immune reaction to provide a pool of effective memory cells, it is blocked in early-stage of memory cells' differentiation (CD45ROlow), probably by tumor-derived suppressive factors. Identifying the molecular and cellular mechanisms behind this suppression can provide invaluable tools for adoptive T cell therapies in cancer. [ABSTRACT FROM AUTHOR]

• About 4–5% of CD4+ lymphocytes in TDLNs of BC had CD4+ CD25− FoxP3+CD127low/− phenotype. • A very small fraction of CD25− cells produce cytokines, lower than regulatory and effector subsets. • CD25− cells display an exhausted phenotype intermediate between effector and regulatory cells. • They have higher expression of IFNγ and IL-2 than Tregs but lower than effector subset. • Expression of IL-10 in this subset is significantly higher than effector but lower than Tregs. A T cell subtype with the CD4+ CD25− FoxP3+ phenotype was recently described. We aimed to investigate the frequency of these cells and their ability to produce cytokines in tumor-draining lymph nodes from patients with breast cancer (BC). Mononuclear cells from lymph nodes of 20 patients with BC were activated and stained for appropriate markers. The cells were assayed with four-color flow cytometry. A very small fraction of CD4+ CD25− FoxP3+ cells produced cytokines at levels that were significantly lower than in the regulatory (CD4+ CD25+ FoxP3+) and effector cell (CD4+ CD25+ FoxP3 −) subpopulations. The expression of IFNγ and IL-2 in the CD4+ CD25− FoxP3+ subset was significantly higher than in Treg cells, but lower than in the effector subset. Conversely, IL-22 expression in Treg cells was significantly higher than in the CD4+ CD25− FoxP3+ subpopulation. The expression of IL-10 in the CD4+ CD25− FoxP3+ subset was also significantly higher than in effector cells. We suggest that CD4+ CD25− FoxP3+ cells in patients with BC are exhausted cells with an intermediate phenotype between effector and regulatory cells. [ABSTRACT FROM AUTHOR]

Purpose: The role of cytokine-producing B cells in antitumor immunity is mostly overlooked. In the present study, we investigated changes in B cell cytokine profiles in breast tumor-draining lymph nodes (TDLNs) during disease progression, and associations of these changes with prognostic indicators. Methods: Flow cytometry was used to measure the expression of TNF-α, IL-10, TGF-β, IL-2 and IFN-γ in B cells from 42 axillary lymph nodes. The frequencies of IL-10+ and FoxP3+ T regulatory cells (Tregs) were also determined. Results: No significant changes in B cell cytokine profiles were observed during breast cancer progression from stage I to III, but the percentage of B cells with high TNF-α expression (TNFhi) showed a negative relationship with lymph node involvement and Her2 expression (p < 0.05). The percentage of IL-10+ B cells was found to be significantly higher in non-metastatic lymph nodes in node-negative compared to node-positive patients (p = 0.001). The frequencies of IL-10+ and TNFhi B cells were found to be negatively correlated with the number of involved lymph nodes. The frequency of TNFhi B cells showed an inverse correlation with the frequency of FoxP3+ Tregs, which in turn was associated with indicators of a poor prognosis. Conclusions: Our data indicate that the cytokine profiles of B cells in TDLNs of patients with breast cancer show associations with various disease parameters. TNFhi and IL-10+ B cells correlated positively with indicators of a good prognosis. Further functional studies are required to elucidate the role of cytokine production by B cells in immunity against breast cancer. [ABSTRACT FROM AUTHOR]

Background: The compartments of memory T cells play a fundamental role in the immune system by substantiating specific and acquired immunity. A new subset of memory cells, T stem cell memory (T) cells, with stem cell-like properties, a high capacity to proliferate, a long survival, and an ability to differentiate into all effector and memory cells has recently been introduced. In the present study, we aimed to determine the frequency of CD4 T and other T memory cell subsets in tumor draining lymph nodes of breast cancer patients. Materials and methods: Mononuclear cells were obtained from axillary lymph nodes of 52 untreated patients with breast cancer (BC) and stained with fluorochrome conjugated anti-CD4, −CCR7, −CD45RO and -CD95 antibodies to detect different subtypes of memory cells in CD4 lymphocyte populations. Data were acquired using a four-color FACSCalibur flow cytometer and analyzed using CellQuest Pro software. Results: We found that >70% of CD4 lymphocytes in draining lymph nodes of BC patients exhibited a memory phenotype of which 7.04 ± 1.04% had a T phenotype (CD4CCR7CD45ROCD95). The frequency of T cells was significantly higher in tumor positive lymph nodes compared to tumor negative lymph nodes ( p = 0.026) as well as among those patients who had at least one affected lymph node ( p = 0.012). Moreover, we found that the total frequency of central memory T cells (T) with a low expression of CD45RO was significantly higher among these patients. The percentage of CD45RO T cells was also found to increase with tumor progression from stage I to stage III ( p = 0.020). On the other hand, we found that the percentage of CD95 effector memory T cells (T) was significantly decreased in involved lymph nodes ( p = 0.009). Conclusion: Our data suggest that following long-term exposure to putative tumor antigens, T cells proliferate to generate a pool of committed memory and effector T cells. As the tumor progresses, the immunosuppressive milieu induced by tumor cells may slow down the differentiation of CD45RO T cells to more functional sub-populations. [ABSTRACT FROM AUTHOR]

Highlights: [•] Accumulation of Tfh, TFR and CD25− Treg cells in tumor draining lymph nodes (TDLNs). [•] In TDLNs, IL17 and IFNγ expression are decreased upon tumor progression. [•] In TDLNs, Treg and Th2 cells are increased in advance stages of disease. [Copyright &y& Elsevier]

The relationship between salivary gland tumors and immune system has not been well inspected. We aimed to investigate the distribution of CD4 + CD25 + Foxp3 + regulatory T (Treg) cells, CTLA4 + CD4 + lymphocytes, as well asIL-17 producing CD4 + and CD8 + (Th17 and Tc17) lymphocytes in peripheral blood of patients with benign and malignant salivary gland tumors and a group of healthy controls. Peripheral blood samples were obtained from 27 patients with salivary gland tumors (19 benign and 8 malignant; mean age of 49.2 ± 18.3), as well as19 age/sex matched healthy donors. Fluorochrome-conjugated antibodies were used to stain the cell surface markers, as well as intracellular molecules following cell-membrane fixation and permeabilization. The stained cells were acquired on a FACSCalibur four-color flowcytometer and analyzed by CellQuest Pro software package. The data were presented as mean percentages ± SEM. Results indicated that the patients with malignant salivary gland tumors have increased percentage of Treg cells (7.74 ± 1.1) and intracellular CTLA4 (inCTLA4)-positive CD4 + lymphocytes (8.18 ± 1.77) in comparison to the patients with benign tumors (4.38 ± 0.56 for Treg cells and 3.83 ± 0.56 for CTLA4 + CD4 + cells), as well as control subjects (2.34 ± 0.28 for Treg cells and 2.22 ± 0.25 for CTLA4 + CD4 + cells) ( p ≤ 0.001). Conversely these patients had reduced percentage of Th17 cells (0.84 ± 0.14) comparing to the patients with benign tumors (2.09 ± 0.31) as well as control subjects (2.31 ± 0.23) ( p ≤ 0.001). In addition, the ratio of Th17/Treg lymphocytes was significantly lower in both malignant (0.12 ± 0.03) and benign (0.48 ± 0.09) tumors in comparison to control subjects (1.26 ± 0.23) ( p < 0.001). The mean percentage of Tc17 cells in patients with benign (1.14 ± 0.15) and malignant (0.60 ± 0.13) tumors was nearly similar to those in control subjects (0.83 ± 0.14) but the mean expression intensityofIL-17 by these cells was significantly higher in patients with malignant tumors (11.06 ± 1.26) than controls (7.61 ± 0.69) ( p = 0.01). Increase in the prevalence of regulatory lymphocytes, Treg cells and CTLA4 + CD4 + lymphocytes, as well as the imbalance of Th17/Treg ratio may suggest the contribution of these immune effector cells in the progression of salivary gland tumors. From immune-regulatory point of view, these data also suggest that benign salivary gland tumors might fall between healthy and malignant conditions. The immunity to salivary gland tumors, as well as the findings presented here merits more in-depth investigation. [ABSTRACT FROM AUTHOR]