Tumor-Infiltrating γδ T Cells Suppress T and Dendritic Cell Function via Mechanisms Controlled by a Unique Toll-like Receptor Signaling Pathway

Summaryγδ T cells are important contributors to innate immunity against cancer, but their regulatory role in controlling immune responses remains largely unknown. Here we report that a dominant γδ1 T cell population among lymphocytes infiltrating breast tumors possessed a potent ability to suppress naive and effector T cell responses and to block the maturation and function of dendritic cells. Adoptive cotransfer experiments demonstrated their in vivo suppressive activity. However, their immunosuppressive activity could be reversed by human Toll-like receptor (TLR) 8 ligands both in vitro and in vivo. siRNA-mediated knockdown experiments revealed that MyD88, TRAF6, IKKα IKKβ, and p38α molecules in γδ1 cells were required for these cells to respond to TLR8 ligands, whereas TAK1, JNK, and ERK molecules did not appear to be involved in functional regulation. These results provide new insights into the regulatory mechanisms of tumor-specific γδ T cells and identify a unique TLR8 signaling pathway linking to their functional regulation

Vasohibin-1 suppresses colon cancer

Vasohibin-1 (VASH1) is an endogenous angiogenesis inhibitor. However, the clinical relevance of VASH1 in colon cancer and its regulations on cancer angiogenesis and cancer cell biological characteristics are still unknown. Here we showed that stromal VASH1 levels were negatively correlated with tumor size, advanced clinical stage and distant metastases in colon cancer patients. Overexpression of VASH1 in colon cancer cells induced apoptosis and senescence, inhibiting cancer cell growth and colony formation in vitro and tumor growth in vivo. In addition, knockdown of VASH1 in cancer cells promoted cell growth, adhesion and migration in vitro, and enhanced tumorigenesis and metastasis in vivo

Tumor-Specific Human CD4+ Regulatory T Cells and Their Ligands Implications for Immunotherapy

AbstractRegulatory T cells play an important role in the maintenance of immunological self-tolerance by suppressing immune responses against autoimmune diseases and cancer. Little is known, however, about the nature of the physiological target antigens for CD4+ regulatory T (Treg) cells. Here we report the identification of the LAGE1 protein as a ligand for tumor-specific CD4+ Treg cell clones generated from the tumor-infiltrating lymphocytes (TILs) of cancer patients. Phenotypic and functional analyses demonstrated that they were antigen-specific CD4+ Treg cells expressing CD25 and GITR molecules and possessing suppressive activity on the proliferative response of naive CD4+ T cells to anti-CD3 antibody stimulation. Ligand-specific activation and cell-cell contact were required for TIL102 Treg cells to exert suppressive activity on CD4+ effector cells. These findings suggest that the presence of tumor-specific CD4+ Treg cells at tumor sites may have a profound effect on the inhibition of T cell responses against cancer

Transport evidence for the surface state and spin-phonon interaction in FeTe0.5_{0.5}Se0.5_{0.5}

The iron chalcogenides have been proved to be intrinsic topological superconductors to implement quantum computation because of their unique electronic structures. The topologically nontrivial surface states of FeTe$_{0.5}$Se$_{0.5}$ have been predicted by several calculations and then confirmed by high-resolution photoemission and scanning tunneling experiments. However, so far, the shreds of the electrical transport evidence for topological surface states are still in absence. By carrying out electrical transport experiments, we observe a topological transition with a nonlinear Hall conductivity and simultaneous linear magnetoresistance near the superconducting transition temperature. Furthermore, we observe a sign reversal of the Hall coefficient accompanied by a concurrently softening of the ${A}_{1g}$ phonon mode at about 40 K, indicating a nematic transition. The synchronized phonon softening with nematicity manifests an enhanced fluctuation state through spin-phonon interaction. Our results solidly corroborate the topological surface states of FeTe$_{0.5}$Se$_{0.5}$ and provide an understanding of the mechanism of the superconductivity in iron chalcogenides.Comment: 10 pages, 8 figure

CD4+ and CD8+ T cells have opposing roles in breast cancer progression and outcome

The Cancer Immunoediting concept has provided critical insights suggesting dual functions of immune system during the cancer initiation and development. However, the dynamics and roles of CD4(+) and CD8(+) T cells in the pathogenesis of breast cancer remain unclear. Here we utilized two murine breast cancer models (4T1 and E0771) and demonstrated that both CD4(+) and CD8(+) T cells were increased and involved in immune responses, but with distinct dynamic trends in breast cancer development. In addition to cell number increases, CD4(+) T cells changed their dominant subsets from Th1 in the early stages to Treg and Th17 cells in the late stages of the cancer progression. We also analyzed CD4(+) and CD8(+) T cell infiltration in primary breast cancer tissues from cancer patients. We observed that CD8(+) T cells are the key effector cell population mediating effective anti-tumor immunity resulting in better clinical outcomes. In contrast, intra-tumoral CD4(+) T cells have negative prognostic effects on breast cancer patient outcomes. These studies indicate that CD4(+) and CD8(+) T cells have opposing roles in breast cancer progression and outcomes, which provides new insights relevant for the development of effective cancer immunotherapeutic approaches

Tumor-Infiltrating γδ T Cells Suppress T and Dendritic Cell Function via Mechanisms Controlled by a Unique Toll-like Receptor Signaling Pathway

Summaryγδ T cells are important contributors to innate immunity against cancer, but their regulatory role in controlling immune responses remains largely unknown. Here we report that a dominant γδ1 T cell population among lymphocytes infiltrating breast tumors possessed a potent ability to suppress naive and effector T cell responses and to block the maturation and function of dendritic cells. Adoptive cotransfer experiments demonstrated their in vivo suppressive activity. However, their immunosuppressive activity could be reversed by human Toll-like receptor (TLR) 8 ligands both in vitro and in vivo. siRNA-mediated knockdown experiments revealed that MyD88, TRAF6, IKKα IKKβ, and p38α molecules in γδ1 cells were required for these cells to respond to TLR8 ligands, whereas TAK1, JNK, and ERK molecules did not appear to be involved in functional regulation. These results provide new insights into the regulatory mechanisms of tumor-specific γδ T cells and identify a unique TLR8 signaling pathway linking to their functional regulation

Metformin improves polycystic ovary syndrome in mice by inhibiting ovarian ferroptosis

Background and objectivePCOS is a common metabolic disorder in women of reproductive age, which pathogenesis is very complex. The role of ferroptosis in PCOS is a novel finding, and the mechanistic studies are not clear. Metformin is a commonly used drug of PCOS but few studies on whether metformin can improve the follicle development and ovarian function in PCOS. We aims to use PCOS mouse model to study the effect of metformin on PCOS based on the ovarian function and explored the regulation of metformin in PCOS mice by intervening in ferroptosis pathway.Materials and methodsC57 BL/6J female mice aged 4-5 weeks were purchased and gavaged with letrozole (1 mg/kg/day) combined with high-fat diet for 21days to establish PCOS model, and control group was set up. After modeling, the mice were divided into PCOS model group and metformin treatment group (Met) (n=6).The Met group were gavaged metformin (200 mg/kg/day) for 28 days. The body weight, estrous cycle, glucose tolerance test (OGTT)and insulin resistance test (ITT) were monitored. Then, The mice were euthanized to collect serum and ovaries. Elisa was used to detect changes in related serum hormones (E2, LH, FSH, TP). Ovaries used for molecular biology experiments to detect changes in GPX4, SIRT3, AMPK/p-AMPK, and mTOR/p-mTOR by Western blot and qPCR.ResultsCompared with the model group mice, body weight was significantly reduced, and their estrous cycle was restored in Met group. The results of OGTT and ITT showed an improvment of glucose tolerance and insulin resistance. Morphological results showed that after metformin treatment, polycystic lesions in ovaries were reduced, the ovarian function was restored, and the expressions of SIRT3 and GPX4 were elevated. WB results demonstrated that the expressions of p-mTOR and p-AMPK in ovaries were significantly reduced in Model group, but reversed in MET group.ConclusionOur study confirmed metformin could not only improve body weight and metabolism disorders, but also improve ovarian dysfunction in PCOS mice.In addition, we explored metformin could regulate ferroptosis to improve PCOS via the SIRT3/AMPK/mTOR pathway. Our study complements the mechanisms by which metformin improves PCOS

iGepros: an integrated gene and protein annotation server for biological nature exploration

<p>Abstract</p> <p>Background</p> <p>In the post-genomic era, transcriptomics and proteomics provide important information to understand the genomes. With fast development of high-throughput technology, more and more transcriptomics and proteomics data are generated at an unprecedented rate. Therefore, requirement of software to annotate those omics data and explore their biological nature arises. In the past decade, some pioneer works were presented to address this issue, but limitations still exist. Fox example, some of these tools offer command line only, which is not suitable for those users with little or no experience in programming. Besides, some tools don’t support large scale gene and protein analysis.</p> <p>Results</p> <p>To overcome these limitations, an integrated gene and protein annotation server named iGepros has been developed. The server provides user-friendly interfaces and detailed on-line examples, so most researchers even those with little or no programming experience can use it smoothly. Moreover, the server provides many functionalities to compare transcriptomics and proteomics data. Especially, the server is constructed under a model-view-control framework, which makes it easy to incorporate more functions to the server in the future.</p> <p>Conclusions</p> <p>In this paper, we present a server with powerful capability not only for gene and protein functional annotation, but also for transcriptomics and proteomics data comparison. Researchers can survey biological characters behind gene and protein datasets and accelerate their investigation of transcriptome and proteome by applying the server. The server is publicly available at <url>http://www.biosino.org/iGepros/</url>.</p