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BACKGROUND: FOXP3 Tregs have been found in breast cancer patients, both humoral and tumor. Survival or prognosis of breast cancer patients seems to correlate with the increase and decrease in FOXP3 Treg. OBJECTIVES: This review aims to provide insights regarding the FOXP3 Tregs involved and their mechanisms in breast cancer prognosis. METHODS: The literature study method is used from primary and secondary libraries. The library search used online-based search instruments such as NCBI-PubMed, Google Scholar, and Elsevier. The data obtained were then arranged according to the framework, data on the relationship between FOXP3 Regulatory T Cells and breast cancer, and writing a journal review was carried out according to the given format. Regulators (Tregs) can inhibit anti-tumor immunity and promote tumor growth. Tregs also play a role in inhibiting cytotoxic T lymphocyte cells by inhibiting the release of granules from CD8+, where CD8+ is important in killing tumor cells. FOXP3 is a Treg-specific biomarker and plays an important role in the development and function of Tregs. RESULTS: Studies on the presence of FOXP3+ Tregs in tumors have shown controversial results. Studies in some tumors reported the presence of FOXP3+, indicating a poor prognosis, whereas studies in other tumors found that FOXP3+ correlated with a good prognosis. CONCLUSION: Regulatory T lymphocytes and TILs in invasive breast carcinoma are still not established. Therefore, further research on the Effect of FOXP3 expression of regulatory T lymphocytes on breast cancer is still important.

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Neoplasias de la Mama , Linfocitos T Reguladores , Humanos , Femenino , Linfocitos T Reguladores/metabolismo , Linfocitos T Reguladores/patología , Neoplasias de la Mama/patología , Pronóstico , Linfocitos Infiltrantes de Tumor , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo

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Hair loss, or alopecia, is associated with several psychosocial and medical comorbidities, and it remains an economic burden to individuals and the society. Alopecia is attributable to varied mechanisms and features a multifactorial predisposition, and the available conventional medical interventions have several limitations. Thus, several therapeutic strategies for alopecia in regenerative medicine are currently being explored, with increasing evidence suggesting that mesenchymal stem cell (MSC) implantation, MSC-derived secretome treatment, and blood-derived platelet-rich plasma therapies are potential treatment options. In this review, we searched the Cochrane Library, MEDLINE (PubMed), EMBASE, and Scopus using various combinations of terms, such as "stem cell," "alopecia," "hair loss," "Androgenetic alopecia," "male-pattern hair loss," "female-pattern hair loss," "regenerative hair growth," "cell therapy," "mesenchymal stem cells," "MSC-derived extracellular vesicles," "MSC-derived exosomes," and "platelet-rich plasma" and summarized the most promising regenerative treatments for alopecia. Moreover, further opportunities of improving efficacy and innovative strategies for promoting clinical application were discussed.

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Systemic lupus erythematosus (SLE) is a global chronic autoimmune disease that invades most organs of the body, with kidney injury being the most prominent feature. Exosomes are extracellular vesicles that carry a variety of proteins, lipids and genetic material, participate in the exchange of local and intersystem information, and play an important immunoregulatory role in a variety of autoimmune diseases. At the same time, the use of exosomes as disease biomarkers and drug delivery carriers also shows great application prospects. This article reviews current progress in the application of exosomes in the pathogenesis, diagnosis and treatment of SLE.

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T regulatory cells suppress a variety of immune responses to self-antigens and play a role in peripheral tolerance maintenance by limiting autoimmune disorders, and other pathological immune responses such as limiting immune reactivity to oncoprotein encoded antigens. Forkhead box P3 (FOXP3) expression is required for Treg stability and affects functional activity. Mutations in the master regulator FOXP3 and related components have been linked to autoimmune diseases in humans, such as IPEX, and a scurfy-like phenotype in mice. Several lines of evidence indicate that Treg use a variety of immunosuppressive mechanisms to limit an immune response by targeting effector cells, including secretion of immunoregulatory cytokines, granzyme/perforin-mediated cell cytolysis, metabolic perturbation, directing the maturation and function of antigen-presenting cells (APC) and secretion of extracellular vesicles for the development of immunological tolerance. In this review, several regulatory mechanisms have been highlighted and discussed.

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Linfocitos T Reguladores/inmunología , Animales , Factores de Transcripción Forkhead/inmunología , Humanos

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Hepatitis B liver infection is caused by hepatitis B virus (HBV) and represents a major global disease problem when it becomes chronic, as is the case for 80-90% of vertical or early life infections. However, in the vast majority (>95%) of adult exposures, the infected individuals are capable of mounting an effective immune response leading to infection resolution. A good understanding of HBV dynamics and the interaction between the virus and immune system during acute infection represents an essential step to characterize and understand the key biological processes involved in disease resolution, which may help to identify potential interventions to prevent chronic hepatitis B. In this work, a quantitative systems pharmacology model for acute hepatitis B characterizing viral dynamics and the main components of the innate, adaptive, and tolerant immune response has been successfully developed. To do so, information from multiple sources and across different organization levels has been integrated in a common mechanistic framework. The final model adequately describes the chronology and plausibility of an HBV-triggered immune response, as well as clinical data from acute patients reported in the literature. Given the holistic nature of the framework, the model can be used to illustrate the relevance of the different immune pathways and biological processes to ultimate response, observing the negligible contribution of the innate response and the key contribution of the cellular response on viral clearance. More specifically, moderate reductions of the proliferation of activated cytotoxic CD8+ lymphocytes or increased immunoregulatory effects can drive the system towards chronicity.

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Dexamethasone is frequently administered to surgical patients for anti-emetic prophylaxis. We have examined the immunomodulatory effects of a single bolus of dexamethasone on circulating peripheral blood mononuclear cells (PBMCs) in the same 10 healthy male volunteers, previously used in our investigation on early in vivo effects of a single anti-emetic dose of dexamethasone on innate immune cell gene expression and activation [1]. Blood samples were drawn at baseline, 2 h, 4 h and 24 h. Immune cell phenotypes were examined with flow cytometry. In this data article the expression strength of markers involved in immune activation and immunosuppression as well as maturation, migration, cell death and responsiveness to signalling on monocyte and cDC subsets, as well as NK cells, CD4+ and CD8+ T cells and regulatory T cells (Treg) are presented. These data improve our understanding of the immunomodulatory effects of the glucocorticoid dexamethasone in-vivo, which may be important for the optimisation of treatment regimens as well as the evaluation of new indications for glucocorticoid treatment.

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INTRODUCTION: Sarcoidosis is a granulomatous systemic disease that becomes chronic in approximately one third of affected patients resulting in quality of life and functional impairment. Immunosuppressive drugs other than steroids represent alternative therapeutic options, but side effects like liver and bone marrow toxicity or increased susceptibility to infections limit their use. Pathophysiological studies in sarcoidosis patients demonstrate altered regulatory T-cell functions with a reduced expression of CTLA-4 (CD152) and prolonged inflammation. Therefore, interfering with CTLA-4 using abatacept might be a therapeutic option in sarcoidosis similar to rheumatoid arthritis therapy. METHODS/DESIGN: This is a multicenter prospective open-labeled single arm phase II study addressing the safety of abatacept in sarcoidosis patients. 30 patients with chronic sarcoidosis requiring immunosuppressive therapy beyond 5 mg prednisolone equivalent will be treated with abatacept in combination with corticosteroids for one year in two centers.The primary endpoint is the number and characterization of severe infectious complications under treatment with abatacept.Secondary endpoints are the rate of all infections, patient-related outcomes (assessed by questionnaires), lung function and immunological parameters including alveolar inflammation assessed by bronchoaveolar lavage. DISCUSSION: This is the first trial of abatacept in patients with sarcoidosis. It is hypothesized that administration of abatacept is safe in patients with chronic sarcoidosis and can limit ongoing inflammation. Patients' wellbeing is assessed by established questionnaires. Immunological work-up will highlight the effect of abatacept on inflammatory pathways in sarcoidosis. TRIAL REGISTRATION: The trial has been registered at the German Clinical Trial Registry (Deutsches Register Klinischer Studien, DRKS) with the identity number DRKS00011660.

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Urticaria is defined as the sudden appearance of erythematous, itchy wheals of variable size, with or without angioedema (AE) (swelling of the deeper layers of the skin). Its classification depends on time course of symptoms and the presence of eliciting factors. When it lasts less than 6 weeks it is classified as acute urticaria (AU), and if the symptoms persist for more than 6 weeks, it is classified as chronic urticaria (CU). Current International Guidelines also classify CU as chronic spontaneous urticaria (CSU) and inducible urticarial, according to the absence or presence of environmental triggering factors. CSU is defined as urticaria and/or angioedema in which there is no evidence of a specific eliciting factor. CSU is associated with autoimmunity in 30-45% of the cases, sharing some immunological mechanisms with other autoimmune diseases, and is associated with autoimmune thyroid disease (ATD) in about 4.3%-57.4% patients. Several studies suggest that adequate therapy with anti-thyroid drugs or levothyroxine in early stages of ATD and CSU, may help to remit the latter; but there is still a lack of double-blind, placebo-controlled studies that support this hypothesis in patients without abnormal thyroid hormone levels. The objective of this review is to describe the pathophysiology of chronic spontaneous urticaria and its association with autoimmune thyroid disease.

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BACKGROUND: Grape phytochemicals prevent intestine-related and subsequent other inflammatory diseases. Phytochemicals and vitamin D are useful for the regulation of inflammatory responses. Phytochemicals is the generic name for terpenoids, carotenoids, and flavonoids that consist of a variety of chemicals contained in vegetables and fruits. There are a variety of grape cultivars that contain many kinds of phytochemicals in their skin and seeds. Grape phytochemicals including Grape Seed Extracts (GSE) have already been used to maintain healthy condition through manipulating inflammatory responses by decreasing the expression of inflammation-related factors. DISCUSSION: Grape phytochemicals mainly consist of a variety of chemicals that include terpenoid (oleanolic acid), carotenoids (ß-carotene, lutein), and flavonoids: flavon-3-ols (quercetin), flavan-3-ols (catechins), anthocyanins, oligomers and polymers (tannins and proanthocyanidins), and resveratrol. Phytochemicals improve the dysbiosis (gut microbiota complication) induced by metabolic syndrome and regulate inflammatory diseases induced by TNF-α production. Once absorbed, flavonoids change into glucuronide-form, move into the bloodstream and reach the inflammatory sites including liver, lung, and sites of arteriosclerosis, where they become active. Furthermore, oleanolic acid acts on TGR5 - the cholic acid receptor, as an agonist of cholic acid. These anti-inflammatory effects of phytochemicals have been proven by the experimental animal studies and the clinical trials. CONCLUSION: It is expected the new health food products will be created from grape skins and seeds since grape phytochemicals participate in the prevention of inflammatory diseases like intestine-related inflammatory diseases.

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Inflamación/prevención & control , Enfermedades Intestinales/prevención & control , Intestinos/efectos de los fármacos , Fitoquímicos/uso terapéutico , Extractos Vegetales/uso terapéutico , Vitis/química , Animales , Frutas/química , Microbioma Gastrointestinal/efectos de los fármacos , Humanos , Intestinos/microbiología , Intestinos/fisiopatología , Semillas/química

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Hepatocellular carcinoma (HCC) is swiftly increasing in prevalence globally with a high mortality rate. The progression of HCC in patients is induced with advanced fibrosis, mainly cirrhosis, and hepatitis. The absence of proper preventive or curative treatment methods encouraged extensive research against HCC to develop new therapeutic strategies. The Food and Drug Administration-approved Nexavar (sorafenib) is used in the treatment of patients with unresectable HCC. In 2017, Stivarga (regorafenib) and Opdivo (nivolumab) got approved for patients with HCC after being treated with sorafenib, and in 2018, Lenvima (lenvatinib) got approved for patients with unresectable HCC. But, owing to the rapid drug resistance development and toxicities, these treatment options are not completely satisfactory. Therefore, there is an urgent need for new systemic combination therapies that target different signaling mechanisms, thereby decreasing the prospect of cancer cells developing resistance to treatment. In this review, HCC etiology and new therapeutic strategies that include currently approved drugs and other potential candidates of HCC such as Milciclib, palbociclib, galunisertib, ipafricept, and ramucirumab are evaluated.

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Background & Aims: Psoriasis and inflammatory bowel disease (IBD) are both chronic inflammatory diseases occurring in the skin and gut, respectively. It is well established that psoriasis and IBD have high concordance rates, and similar changes in immune cells and microbiome composition have been reported in both conditions. To study this connection, we used a combination murine model of psoriatic dermatitis and colitis in which mice were treated topically with the Toll-like receptor 7 agonist imiquimod (IMQ) and fed dextran sulfate sodium (DSS). Methods: We applied IMQ topically to B6 mice (IMQ mice) and subsequently fed them 2% DSS in their drinking water. Disease activity and immune cell phenotypes were analyzed, and the microbial composition of fecal samples was investigated using 16S ribosomal RNA sequencing. We transplanted feces from IMQ mice to germ-free IQI/Jic (IQI) mice and fed them DSS to assess the effect of the gut microbiome on disease. Results: We first confirmed that IMQ mice showed accelerated DSS colitis. IMQ mice had decreased numbers of IgD+ and IgM+ B cells and increased numbers of non-cytokine-producing macrophages in the gut. Moreover, the gut microbiomes of IMQ mice were perturbed, with significant reductions of Lactobacillus johnsonii and Lactobacillus reuteri populations. Germ-free mice transplanted with feces from IMQ mice, but not with feces from untreated mice, also developed exacerbated DSS colitis. Conclusions: These results suggest that skin inflammation may contribute to pathogenic conditions in the gut via immunologic and microbiological changes. Our finding of a novel potential skin-gut interaction provides new insights into the coincidence of psoriasis and IBD.

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Colitis/inmunología , Colitis/microbiología , Dermatitis/complicaciones , Microbioma Gastrointestinal , Receptor Toll-Like 7/agonistas , Animales , Linfocitos B/inmunología , Movimiento Celular , Colitis/inducido químicamente , Colitis/patología , Dermatitis/inmunología , Sulfato de Dextran , Progresión de la Enfermedad , Trasplante de Microbiota Fecal , Femenino , Células Madre Hematopoyéticas/metabolismo , Imiquimod/efectos adversos , Inmunoglobulina D/metabolismo , Inmunoglobulina M/metabolismo , Intestinos/inmunología , Intestinos/patología , Lactobacillus/fisiología , Ganglios Linfáticos/patología , Depleción Linfocítica , Ratones Endogámicos C57BL , Permeabilidad , Psoriasis/complicaciones , Psoriasis/inmunología

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AIM OF STUDY: Nasopharyngeal carcinoma (NPC) is by far the most common malignant tumor of the nasopharynx and is suggested to be related to immune system dysfunction. T cells play a central role in the cell-mediated immunity. However, how the T cells vary during the NPC treatment is still unclear. MATERIALS AND METHODS: We divided the NPC patients into previously untreated, partial remission, complete remission, and relapse groups. Healthy controls were those without any autoimmune diseases, cancer, or recent infection. We used flow cytometry to detect the changes in T cell subsets. RESULTS: We found the quantity (%) of CD4+ CD25+ CD127low/- Treg regulatory T cells and CD8+ CD28- T cells were obviously increased in NPC previously untreated, partial remission, and relapse groups. There was no difference in these two subsets between complete remission groups and healthy controls. In addition, the quantity (%) of CD3+ CD4+ and CD8+ CD28+ effector T cells were reduced in NPC previously untreated, partial remission, and relapse groups. There was no difference in these two subsets between complete remission groups and healthy controls. CONCLUSIONS: Our research determines the changes of T cell subsets in different stages of NPC.

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Carcinoma/inmunología , Carcinoma/patología , Citometría de Flujo/métodos , Neoplasias Nasofaríngeas/inmunología , Neoplasias Nasofaríngeas/patología , Subgrupos de Linfocitos T/inmunología , Linfocitos T Reguladores/inmunología , Adolescente , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Carcinoma Nasofaríngeo , Pronóstico , Adulto Joven

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Thymic stromal lymphopoietin (TSLP) was identified more than 20 years ago as a secreted factor of a mouse thymic stromal cell line; later, a human orthologue was also identified. The signaling pathway triggered by TSLP has been extensively studied, and upregulation of the cytokine itself is linked to the pathogenesis of numerous Th2-related diseases, including atopic dermatitis, asthma, allergic responses, as well as certain types of cancers. On the other hand, TSLP mediates several immune homeostatic functions in both the gut and the thymus. Thus, a paradox occurs; why is TSLP homeostatic in certain tissues and a hallmark of exacerbated Th2 responses in the aforementioned pathologies? We and others have recently shown that in humans a novel isoform exists; this is a shorter isoform of TSLP whose expression is constitutive and controlled by a separate promoter. Short TSLP isoform mediates the homeostatic functions, whereas the long isoform is expressed at low/undetectable level at steady state and upregulated during inflammation in several tissues. Here we review the most recent data concerning the differential expression of the 2 isoforms and provide a potential explanation to the paradox. TSLP is regarded as a promising target for treatment of relevant pathologies, with a number of clinical trials already underway. It is important to design new strategies aimed at leaving intact the homeostatic effects of the short isoform while targeting the inflammatory effects of the long isoform.

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The revival of cancer immunotherapy has taken place with the clinical success of immune checkpoint inhibition. However, the spectrum of immunotherapeutic approaches is much broader encompassing T cell engaging strategies, tumour-specific vaccination, antibodies or immunocytokines. This review focuses on the immunological effects of irradiation and the evidence available on combination strategies with immunotherapy. The available data suggest great potential of combined treatments, yet also poses questions about dose, fractionation, timing and most promising multimodal strategies.

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BACKGROUND & AIMS: Most knowledge about gastrointestinal (GI)-tract dendritic cells (DC) relies on murine studies where CD103+ DC specialize in generating immune tolerance with the functionality of CD11b+/- subsets being unclear. Information about human GI-DC is scarce, especially regarding regional specifications. Here, we characterized human DC properties throughout the human colon. METHODS: Paired proximal (right/ascending) and distal (left/descending) human colonic biopsies from 95 healthy subjects were taken; DC were assessed by flow cytometry and microbiota composition assessed by 16S rRNA gene sequencing. RESULTS: Colonic DC identified were myeloid (mDC, CD11c+CD123-) and further divided based on CD103 and SIRPα (human analog of murine CD11b) expression. CD103-SIRPα+ DC were the major population and with CD103+SIRPα+ DC were CD1c+ILT3+CCR2+ (although CCR2 was not expressed on all CD103+SIRPα+ DC). CD103+SIRPα- DC constituted a minor subset that were CD141+ILT3-CCR2-. Proximal colon samples had higher total DC counts and fewer CD103+SIRPα+ cells. Proximal colon DC were more mature than distal DC with higher stimulatory capacity for CD4+CD45RA+ T-cells. However, DC and DC-invoked T-cell expression of mucosal homing markers (ß7, CCR9) was lower for proximal DC. CCR2 was expressed on circulating CD1c+, but not CD141+ mDC, and mediated DC recruitment by colonic culture supernatants in transwell assays. Proximal colon DC produced higher levels of cytokines. Mucosal microbiota profiling showed a lower microbiota load in the proximal colon, but with no differences in microbiota composition between compartments. CONCLUSIONS: Proximal colonic DC subsets differ from those in distal colon and are more mature. Targeted immunotherapy using DC in T-cell mediated GI tract inflammation may therefore need to reflect this immune compartmentalization.

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Melanoma patients are at a high risk of developing brain metastases, which are strongly vascularized and therefore have a significant risk of spontaneous bleeding. VEGF not only plays a role in neo-angiogenesis but also in the antitumor immune response. VEGFR-targeted therapy might not only have an impact on the tumor vascularization but also on tumor-infiltrating immune cells. In this study, we investigated the effect of axitinib, a small molecule TKI of VEGFR-1, -2, and -3, on tumor growth and on the composition of tumor-infiltrating immune cells in subcutaneous and intracranial mouse melanoma models. In vivo treatment with axitinib induced a strong inhibition of tumor growth and significantly improved survival in both tumor models. Characterization of the immune cells within the spleen and tumor of tumor-bearing mice respectively showed a significant increase in the number of CD3+CD8+ T cells and CD11b+ cells of axitinib-treated mice. More specifically, we observed a significant increase of intratumoral monocytic myeloid-derived suppressor cells (moMDSCs; CD11b+Ly6ChighLy6G-). Interestingly, in vitro proliferation assays showed that moMDSCs isolated from spleen or tumor of axitinib-treated mice had a reduced suppressive capacity on a per cell basis as compared to those isolated from vehicle-treated mice. Moreover, MDSCs from axitinib-treated animals displayed the capacity to stimulate allogeneic T cells. Thus, treatment with axitinib induces differentiation of moMDSC toward an antigen-presenting phenotype. Based on these observations, we conclude that the impact of axitinib on tumor growth and survival is most likely not restricted to direct anti-angiogenic effects but also involves important effects on tumor immunity.

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Excessive nutrient intake in obesity triggers the accumulation of various types of immune cells in adipose tissue, particularly visceral adipose tissue (VAT). This can result in chronic inflammation which disrupts insulin effects on adipocytes and muscle cells and culminates in development of insulin resistance. The interplay between immune cells and adipose tissue is a key event for the development of insulin resistance that precedes type 2 diabetes. CD40, a well-documented costimulatory receptor, is required for efficient systemic adaptive immune responses. However, we and other groups recently showed that CD40 unexpectedly ameliorates inflammation in VAT and accordingly attenuates obesity-induced insulin resistance. Specifically, although CD40 is typically considered to play its principal immune roles on B lymphocytes and myeloid cells, we found that CD40(+)CD8(+) T lymphocytes were major contributors to the protective effect. This unexpected inhibitory role of CD40 on CD8(+) T cell activation in VAT may reflect unique features of this microenvironment. Additional knowledge gaps include whether CD40 also plays roles in mucosal immunity that control the homeostasis of gut microbiota, and human metabolic diseases. Potential therapeutic approaches, including stimulating CD40 signaling and/or manipulating specific CD40 signaling pathways in the VAT microenvironment, may open new avenues for treatment of obesity-induced insulin resistance, and prevention of type 2 diabetes.

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Gastrointestinal stromal tumors (GIST) are the most frequently occurring digestive sarcomas. The prognosis of localized GIST is heterogeneous, notably for patients with an Armed Forces Institute of Pathology (AFIP) intermediate or high risk of relapse. Despite imatinib effectiveness, it is crucial to develop therapies able to overcome the resistance mechanisms. The immune system represents an attractive prognostic and therapeutic target. The Programmed cell Death 1 (PD1)/programmed cell death ligand 1 (PDL1) pathway is a key inhibitor of the immune response; recently, anti-PD1 and anti-PDL1 drugs showed very promising results in patients with solid tumors. However, PDL1 expression has never been studied in GIST. Our objective was to analyze PDL1 expression in a large series of clinical samples. We analyzed mRNA expression data of 139 operated imatinib-untreated localized GIST profiled using DNA microarrays and searched for correlations with histoclinical features including postoperative metastatic relapse. PDL1 expression was heterogeneous across tumors and was higher in AFIP low-risk than in high-risk samples, and in samples without than with metastatic relapse. PDL1 expression was associated with immunity-related parameters such as T-cell-specific and CD8+ T-cell-specific gene expression signatures and probabilities of activation of interferon α (IFNα), IFNγ, and tumor necrosis factor α (TNFα) pathways, suggesting positive correlation with a cytotoxic T-cell response. In multivariate analysis, the PDL1-low group was associated with a higher metastatic risk independently of the AFIP classification and the KIT mutational status. In conclusion, PDL1 expression refines the prediction of metastatic relapse in localized GIST and might improve our ability to better tailor adjuvant imatinib. In the metastatic setting, PDL1 expression might guide the use of PDL1 inhibitors, alone or associated with tyrosine kinase inhibitors.

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There is increased production of plasmacytoid dendritic cells (pDCs) in the bone marrow (BM) of multiple myeloma (MM) patients and these favor Th22 cell differentiation. Here, we found that the frequency of interleukin (IL)-22+IL-17-IL-13+ T cells is significantly increased in peripheral blood (PB) and BM of stage III and relapsed/refractory MM patients compared with healthy donors and patients with asymptomatic or stage I/II disease. Th22 cells cloned from the BM of MM patients were CCR6+CXCR4+CCR4+CCR10- and produced IL-22 and IL-13 but not IL-17. Furthermore, polyfunctional Th22-Th2 and Th22-Th1 clones were identified based on the co-expression of additional chemokine receptors and cytokines (CRTh2 or CXCR3 and IL-5 or interferon gamma [IFNγ], respectively). A fraction of MM cell lines and primary tumors aberrantly expressed the IL-22RA1 and IL-22 induced STAT-3 phosphorylation, cell growth, and resistance to drug-induced cell death in MM cells. IL-13 treatment of normal BM mesenchymal stromal cells (MSCs) induced STAT-6 phosphorylation, adhesion molecule upregulation, and increased IL-6 production and significantly favored MM cell growth compared with untreated BM MSCs. Collectively, our data show that increased frequency of IL-22+IL-17-IL-13+ T cells correlates with poor prognosis in MM through IL-22 and IL-13 protumor activity and suggest that interference with IL-22 and IL-13 signaling pathways could be exploited for therapeutic intervention.

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Conventional treatment for cancer routinely includes surgical resection and some combination of chemotherapy and radiation. These approaches are frequently accompanied by unintended and highly toxic collateral damage to healthy tissues, which are offset by only marginal prognostic improvements in patients with advanced cancers. This unfortunate balance has driven the development of novel therapies that aim to target tumors both safely and efficiently. Over the past decade, mounting evidence has supported the therapeutic utility of T-cell-centered cancer immunotherapy, which, in its various iterations, has been shown capable of eliciting highly precise and robust antitumor responses both in animal models and human trials. The identification of tumor-specific targets has further fueled a growing interest in T-cell therapies given their potential to circumvent the non-specific nature of traditional treatments. Of the several strategies geared toward achieving T-cell recognition of tumor, bispecific antibodies (bsAbs) represent a novel class of biologics that have garnered enthusiasm in recent years due to their versatility, specificity, safety, cost, and ease of production. Bispecific T-cell Engagers (BiTEs) are a subclass of bsAbs that are specific for CD3 on one arm and a tumor antigen on the second. As such, BiTEs function by recruiting and activating polyclonal populations of T-cells at tumor sites, and do so without the need for co-stimulation or conventional MHC recognition. Blinatumomab, a well-characterized BiTE, has emerged as a promising recombinant bscCD19×CD3 construct that has demonstrated remarkable antitumor activity in patients with B-cell malignancies. This clinical success has resulted in the rapid extension of BiTE technology against a greater repertoire of tumor antigens and the recent US Food and Drug Administration's (FDA) accelerated approval of blinatumomab for the treatment of a rare form of acute lymphoblastic leukemia (ALL). In this review, we dissect the role of T-cell therapeutics in the new era of cancer immunotherapy, appraise the value of CAR T-cells in the context of solid tumors, and discuss why the BiTE platform may rescue several of the apparent deficits and shortcomings of competing immunotherapies to support its widespread clinical application.