Search results for "checkpoint"
showing 10 items of 311 documents
Immunobiology of Uveal Melanoma: State of the Art and Therapeutic Targets
2019
Uveal Melanoma (UM) represents the most common primary intraocular malignant tumor in adults. Although it originates from melanocytes as cutaneous melanoma, it shows significant clinical and biological differences with the latter, including high resistance to immune therapy. Indeed, UM can evade immune surveillance via multiple mechanisms, such as the expression of inhibitory checkpoints (e.g., PD-L1, CD47, CD200) and the production of IDO-1 and soluble FasL, among others. More in-depth understanding of these mechanisms will suggest potential targets for the design of novel and more effective management strategies for UM patients.
Analysis of the Gut Microbiota: An Emerging Source of Biomarkers for Immune Checkpoint Blockade Therapy in Non-Small Cell Lung Cancer
2021
Simple Summary The immune checkpoint blockade (ICB), and concretely the blockade of the PD1/PDL1 axis, has opened up a new standard of treatment for non-small cell lung cancer (NSCLC). However, despite substantial advances in clinical care, many patients still remain refractory to these therapies. Biomarkers such as PD-L1 expression and tumor mutational burden have been associated with ICB efficacy, but the mechanisms underlying variable responses are not yet fully understood. Recently, the differential composition of the gut microbiota was studied as one of the variables accounting for interpatient heterogeneity in ICB responses. To better understand the potential role of the gut microbiot…
Immune checkpoint blockade for Merkel cell carcinoma: actual findings and unanswered questions
2019
Purpose: Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine carcinoma arising from the skin. We aimed to review and deal with some of the most relevant controversial topics on the correct use of immunotherapy for the treatment of MCC. Methods: The primary search was carried out via PubMed, EMBASE, and the Cochrane Library (until 31st May, 2018), while other articles and guidelines were retrieved from related papers or those referenced in these papers. Additionally, we performed an extensive search on ClinicalTrials.gov to gather information on the ongoing clinical trials related to this specific topic. Results: We performed an up-to-date critical review taking into account the…
Vγ9Vδ2 T Cells as Strategic Weapons to Improve the Potency of Immune Checkpoint Blockade and Immune Interventions in Human Myeloma
2018
The advent of immune checkpoint (ICP) blockade has introduced an unprecedented paradigm shift in the treatment of cancer. Though very promising, there is still a substantial proportion of patients who do not respond or develop resistance to ICP blockade. In vitro and in vivo models are eagerly needed to identify mechanisms to maximize the immune potency of ICP blockade and overcome primary and acquired resistance to ICP blockade. Vγ9Vδ2 T cells isolated from the bone marrow (BM) from multiple myeloma (MM) are excellent tools to investigate the mechanisms of resistance to PD-1 blockade and to decipher the network of mutual interactions between PD-1 and the immune suppressive tumor microenvir…
Role of Hypoxia and the Adenosine System in Immune Evasion and Prognosis of Patients with Brain Metastases of Melanoma: A Multiplex Whole Slide Immun…
2020
Simple Summary The introduction of immune-checkpoint inhibitors improved the therapeutic landscape for patients with advanced malignant melanoma. However, many patients, including patients with melanoma brain metastases, do not derive benefit from immune-checkpoint blockade. Hence, biomarkers are needed to identify potential mechanisms of resistance and optimize patient selection. This study aimed to explore the role of hypoxia-mediated immunosuppression within the tumor microenvironment of patients with metastatic melanoma using multiplex immunofluorescence. We analyzed the prognostic relevance of the hypoxia surrogate marker GLUT-1, the adenosine-synthesizing ectoenzymes CD73/CD39, and th…
Integrative analysis of key candidate genes and signaling pathways in autoimmune thyroid dysfunction related to anti-CTLA-4 therapy by bioinformatics
2020
Summary Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), the first immune checkpoint to be targeted clinically, has provided an effective treatment option for various malignancies. However, the clinical advantages associated with CTLA-4 inhibitors can be offset by the potentially severe immune-related adverse events (IRAEs), including autoimmune thyroid dysfunction. To investigate the candidate genes and signaling pathways involving in autoimmune thyroid dysfunction related to anti-CTLA-4 therapy, integrated differentially expressed genes (DEGs) were extracted from the intersection of genes from Gene Expression Omnibus (GEO) datasets and text mining. The functional enrichment was perfo…
Antiproliferative effect of plant sterols at colonic concentrations on Caco-2 cells
2017
Abstract Plant sterols (PS) have been incorporated to foods due to their cholesterol-lowering effect. Because of their low intestinal absorption (0.5–2%), they can reach the colon and exert local actions. The aim of this study was to evaluate the antiproliferative effect of individual (β-sitosterol, campesterol and stigmasterol) and combined PS in colon cancer cells (Caco-2) at human colonic concentrations after simulated gastrointestinal digestion of a PS enriched milk-based fruit beverage. β-Sitosterol, campesterol and stigmasterol induced significant cell viability reduction (13–59% vs control), but only stigmasterol produced an overproduction of reactive oxygen species (92% vs control).…
Synthesis and antiproliferative activity of a natural like glycoconjugate polycyclic compound
2016
Abstract A natural like O -glycoconjugate polycyclic compound 4 was obtained by a multistep procedure starting from N -(3-methyl-1-(4-nitrophenyl)-1 H -pyrazol-5-yl)acetamide. The glycosyl derivative 4 showed antiproliferative activity against all the tumoral cell lines of the NCI panel in the range 0.47–5.43 μ M. Cytofluorimetric analysis performed on MDA-MB231, a very aggressive breast cancer cell line, which does not express estrogen, progesterone and HER-2/neu receptors, showed that 4 is able to induce prolonged cell cycle arrest at G2/M phase and morphological signs of differentiation. These events are correlated with down-regulation of both cyclin B1 and cdc2, the cyclins involved in…
CHK1 inhibitor sensitizes resistant colorectal cancer stem cells to nortopsentin
2021
Summary Limited therapeutic options are available for advanced colorectal cancer (CRC). Herein, we report that exposure to a neo-synthetic bis(indolyl)thiazole alkaloid analog, nortopsentin 234 (NORA234), leads to an initial reduction of proliferative and clonogenic potential of CRC sphere cells (CR-CSphCs), followed by an adaptive response selecting the CR-CSphC-resistant compartment. Cells spared by the treatment with NORA234 express high levels of CD44v6, associated with a constitutive activation of Wnt pathway. In CR-CSphC-based organoids, NORA234 causes a genotoxic stress paralleled by G2-M cell cycle arrest and activation of CHK1, driving the DNA damage repair of CR-CSphCs, regardless…
Physiological concentrations of phytosterols enhance the apoptotic effects of 5-fluorouracil in colon cancer cells
2018
Abstract Combining natural products as co-adjuvants in 5-fluorouracil (5-FU) chemotherapy might enhance the effectiveness of 5-FU by avoiding a high dosage and/or reducing treatment times. We explored the anticancer efficacy of the phytosterols (PS) at concentrations achievable in the human colon, as well as their potential as sensitizing agents of human colon cancer cells (Caco-2 and HT-29) to 5-FU treatment. Cells proliferation, combination index, cell cycle, apoptosis, caspases activation, ROS production, and ΔΨm were determined. Co-treatment (PS+5-FU) had an antiproliferative additive effect, and moreover, in general a significantly improved efficacy was observed on cell cycle arrest at…