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Targeting Intercellular Communication in the Bone Microenvironment to Prevent Disseminated Tumor Cell Escape from Dormancy and Bone Metastatic Tumor Growth.

Metastasis to the bone is a common feature of many cancers including those of the breast, prostate, lung, thyroid and kidney. Once tumors metastasize to the bone, they are essentially incurable. Bone metastasis is a complex process involving not only intravasation of tumor cells from the primary tumor into circulation, but extravasation from circulation into the bone where they meet an environment that is generally suppressive of their growth. The bone microenvironment can inhibit the growth of disseminated tumor cells (DTC) by inducing dormancy of the DTC directly and later on following forma

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… It has been shown that TGF-β induces downregulation of key factors involved in cytotoxic T cell-mediated cytotoxicity, including perforin, granzyme A, granzyme B, Fas ligand, and interferon gamma [ 177 ]. …

Mechanisms, Diagnosis and Treatment of Bone Metastases.

Bone and bone marrow are among the most frequent metastatic sites of cancer. The occurrence of bone metastasis is frequently associated with a dismal disease outcome. The prevention and therapy of bone metastases is a priority in the treatment of cancer patients. However, current therapeutic options for patients with bone metastatic disease are limited in efficacy and associated with increased morbidity. Therefore, most current therapies are mainly palliative in nature. A better understanding of the underlying molecular pathways of the bone metastatic process is warranted to develop novel, wel

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… NK cells represent another important cell type in immune-mediated tumor killing through granzyme B- and perforin-mediated apoptosis or Fas–Fas ligand interactions. Depletion of NK cells causes uncontrolled tumor growth and metastasis. …

Role of Telomeres and Telomeric Proteins in Human Malignancies and Their Therapeutic Potential.

Telomeres are the ends of linear chromosomes comprised of repetitive nucleotide sequences in humans. Telomeres preserve chromosomal stability and genomic integrity. Telomere length shortens with every cell division in somatic cells, eventually resulting in replicative senescence once telomere length becomes critically short. Telomere shortening can be overcome by telomerase enzyme activity that is undetectable in somatic cells, while being active in germline cells, stem cells, and immune cells. Telomeres are bound by a shelterin complex that regulates telomere lengthening as well as protects t

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… Immunized monkeys showed strong IFN-γ and perforin release, indicating that phTERT exhibited potential cytotoxicity. …

Bispecific Antibodies for Multiple Myeloma: A Review of Targets, Drugs, Clinical Trials, and Future Directions.

Multiple myeloma (MM) is a plasma cell malignancy and the second most common hematological neoplasm in adults, comprising 1.8% of all cancers. With an annual incidence of ~30,770 cases in the United States, MM has a high mortality rate, leading to 12,770 deaths per year. MM is a genetically complex, highly heterogeneous malignancy, with significant inter- and intra-patient clonal variability. Recent years have witnessed dramatic improvements in the diagnostics, classification, and treatment of MM. However, patients with high-risk disease have not yet benefited from therapeutic advances. High-r

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… Cytokines (i.e., IFN-g, IL-2, IL-6, TNF-a) and cytolytic enzymes (i.e., granzyme B and perforin) are released, resulting in MM cell death. …

Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune effector cell-related adverse events.

Immune effector cell (IEC) therapies offer durable and sustained remissions in significant numbers of patients with hematological cancers. While these unique immunotherapies have improved outcomes for pediatric and adult patients in a number of disease states, as 'living drugs,' their toxicity profiles, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), differ markedly from conventional cancer therapeutics. At the time of article preparation, the US Food and Drug Administration (FDA) has approved tisagenlecleucel, axicabtagene ciloleuc

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): part one : National Harbor, MD, USA. 9-13 November 2016

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Evolving Paradigms in Chronic Graft-Versus-Host Disease: From Global Immunosuppression to Precision Targeted and Cell-Based Therapies.

Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is a well-established treatment for a range of medical conditions. However, the procedure carries with it a significant risk of chronic graft-versus-host disease (cGVHD), which can have a considerable impact on patients’ quality of life and clinical outcomes. In recent years, there has been a marked shift in treatment strategies for this condition, with greater emphasis being placed on novel targeted therapies and cell therapies that target specific pathways. This shift in approach signifies a more profound comprehension of the pa

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… The direct destruction of host cells by these activated T cells is achieved through the release of perforin, granzyme, and Fas/FasL-mediated apoptotic signals [ 30 , 31 ]. …

Development of CAR T Cell Therapy in Children-A Comprehensive Overview.

CAR T cell therapy has revolutionized immunotherapy in the last decade with the successful establishment of chimeric antigen receptor (CAR)-expressing cellular therapies as an alternative treatment in relapsed and refractory CD19-positive leukemias and lymphomas. There are fundamental reasons why CAR T cell therapy has been approved by the Food and Drug administration and the European Medicines Agency for pediatric and young adult patients first. Commonly, novel therapies are developed for adult patients and then adapted for pediatric use, due to regulatory and commercial reasons. Both strateg

"Complimenting the Complement": Mechanistic Insights and Opportunities for Therapeutics in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and a leading cause of death in the US and worldwide. HCC remains a global health problem and is highly aggressive with unfavorable prognosis. Even with surgical interventions and newer medical treatment regimens, patients with HCC have poor survival rates. These limited therapeutic strategies and mechanistic understandings of HCC immunopathogenesis urgently warrant non-palliative treatment measures. Irrespective of the multitude etiologies, the liver microenvironment in HCC is intricately associated with chronic

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… Similarly, increased accumulation of Tregs in HCC tumors correlated with reduced CD8 + T-cell infiltrations and reduced Granzyme A, Granzyme B, and Perforin expressions. Importantly, these events are associated with significantly reduced survival times and increased mortality of HCC patients. …

Ход работы сессии 28th Европейский конгресс педиатрической ремуматологии (ПСР) 2022) Прага, Чешская Республика. 20-23 сентябрь 2022.

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… Objectives: We wished to test how two independent and synergistic susceptibility factors, perforin insufficiency and excess IL-18, drove pathology in a spontaneous murine model of HLH/MAS. … Conclusion: Both perforin deficiency and excess IL-18 seem to exert preferential effects on post-thymically activated CD8 T-cells in reticuloendothelial organs. These are precisely the sites where hemophagocytosis is most commonly observed. …

Application of dendritic cell extracellular vesicles as a valid nanoparticle platform for cancer therapies: a narrative review.

The prevalence of cancers has actually increased during the last few decades, affecting almost all human societies. Despite progress in therapeutic protocols, cancer is still the main cause of global human mortality. Although the advancement of modern immunotherapeutic approaches can increase the survival rate of cancer patients, new modalities are essential for improved therapeutic outcomes. Extracellular vesicles (EVs) are nanosized particles and are used for cell-free approaches instead of direct whole cell-based administration. It has been thought that EVs can reduce the risks and side eff

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… Activated cytotoxic T cells (CD8 + ) subsequently target and eliminate cancer cells through highly specific cytotoxic mechanisms, such as granzyme and perforin release, leading to tumor cell apoptosis. … Activated cytotoxic T cells (CD8 + ) subsequently target and eliminate cancer cells through highly specific cytotoxic mechanisms, such as granzyme and perforin release, leading to tumor cell apoptosis. …

Декодирование GPCR, сигнализирующее перепрограммирование рака: молекулярные механизмы и терапевтические последствия.

G белковые рецепторы (GPCR) представляют собой крупнейшую мембранную группу рецепторов в геноме человека и служат ключевыми регуляторами клеточного сигнала, гомеостаза и фармакологической реакции. Помимо их классической роли в посредничестве внеклеточной стимуляции по зависящим от G-протеина и независимым путям, которые играют ключевую роль при помощи GPCR сигнальных путей, включая CAMP-PKA/EPAC, IP3/PLC, PI3K/Akt/mTOR и ERK/MAPK cascades, в вождении онкогенного распространения, апоптоза и метастаза. Кроме того, ГПХР замешаны в опухоли с помощью различных молекулярных механизмов, в рамках кото

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… extracellular architecture positions the antigenic epitope of GPRC5D in close proximity to the plasma membrane, which has important functional implications for therapeutic targeting, allowing a spatial configuration that enhances T-cell activation and promotes effective cytotoxic responses mediated by perforin …

Convergence of mRNA technology and chimeric antigen receptor therapy: targeted technology optimizing targeted therapy.

Engineering cells to express chimeric antigen receptors (CARs) represents a novel approach in cancer immunotherapy, demonstrating remarkable efficacy in the treatment of hematologic malignancies while also encountering numerous challenges. Against the backdrop of the widespread application of COVID-19 mRNA vaccines, the integration of mRNA technology to produce CAR cells and enhance CAR therapies marks the cutting edge of cancer treatment innovation, offering potential solutions to the challenges faced by traditional CAR therapies. This convergence offers distinct advantages. It enables the ge

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… Compared to UCB-NK, CD19 CAR-NK, and CD20 CAR-NK cells, mRNA-based CD19/CD20 dual-targeted CAR-NK cells exhibit increased specific cytotoxicity against acute lymphoblastic leukemia (ALL) and elevated release levels of cytokines such as perforin, IFN-γ, and IL-15 [ 77 ]. …

Immunoglobulin A Nephropathy: Molecular Pathogenesis and Targeted Therapy.

Immunoglobulin A nephropathy (IgAN), the most prevalent primary glomerulonephritis globally, is characterized by mesangial IgA deposition and heterogeneous clinical trajectories. Historically, management relied on renin-angiotensin system inhibition and empirical immunosuppression, yet high lifetime kidney failure risk persists despite optimized care. This review synthesizes advances in molecular pathogenesis, highlighting how the traditional multi-hit hypothesis-while foundational for targeted therapy development-fails to capture IgAN's recurrent, self-amplifying nature. We introduce the "spi

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… , platelet‐derived growth factor receptor β (PDGFRβ) | Genetically engineered T‐cells expressing chimeric antigen receptors (CARs) targeting B‐cell/plasma cell surface antigens and targeting surface antigen of extracellular matrix (ECM)‐producing cells in the kidney; induces direct cytotoxicity via perforin …

Tumor cell plasticity in targeted therapy-induced resistance: mechanisms and new strategies.

Despite the success of targeted therapies in cancer treatment, therapy-induced resistance remains a major obstacle to a complete cure. Tumor cells evade treatments and relapse via phenotypic switching driven by intrinsic or induced cell plasticity. Several reversible mechanisms have been proposed to circumvent tumor cell plasticity, including epigenetic modifications, regulation of transcription factors, activation or suppression of key signaling pathways, as well as modification of the tumor environment. Epithelial-to-mesenchymal transition, tumor cell and cancer stem cell formation also serv

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… lactate and the subsequently increased HGF then activate the MET signaling pathway in cancer cells and cause resistance to erlotinib. 175 – 177 Moreover, hypoxia-induced glycolysis represses natural killer (NK) cells via lactate accumulation and reduces cytotoxicity by decreased level of NKG2D, CD16, perforin …

Future perspectives in melanoma research: meeting report from the "Melanoma Bridge", Napoli, December 5th-8th 2013.

The fourth "Melanoma Bridge Meeting" took place in Naples, December 5 to 8th, 2013. The four topics discussed at this meeting were: Diagnosis and New Procedures, Molecular Advances and Combination Therapies, News in Immunotherapy, and Tumor Microenvironment and Biomarkers.

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… Tim-3 + Tregs secrete perforin and granzymes A and B as cytotoxic effector molecules to kill or deliver a negative signal to responder T cells. Tim-3/PD-L1 blockade in vivo down-modulates genes associated with Tregs suppressor function. …

Cancer Immunotherapy in Combination with Radiotherapy and/or Chemotherapy: Mechanisms and Clinical Therapy.

Since the United States Food and Drug Administration approved the first immune checkpoint inhibitor ipilimumab for metastatic melanoma in 2011, ICIs have been approved for a range of cancers and significantly improving treatment outcomes. However, the objective response rate of ICI monotherapy remains modest (10-40%), with clinical benefit observed in only 15-20% of patients. The limited efficacy of ICIs in many patients is often attributed to poorly immunogenic ("cold") tumors. Radiotherapy and chemotherapy exhibit immunomodulatory properties that can enhance tumor immunogenicity. These effec

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… However, extending this to two successive 6‐day cycles of CTX paradoxically led to increased infiltration of Foxp3⁺ Treg cells and reduced expression of cytolytic effector molecule perforin within the TME—suggesting a rebound in immunosuppressive dominance [ 365 , 366 ]. …

Efficacy and safety of bispecific antibodies vs. immune checkpoint blockade combination therapy in cancer: a real-world comparison.

Emerging tumor immunotherapy methods encompass bispecific antibodies (BSABs), immune checkpoint inhibitors (ICIs), and adoptive cell immunotherapy. BSABs belong to the antibody family that can specifically recognize two different antigens or epitopes on the same antigen. These antibodies demonstrate superior clinical efficacy than monoclonal antibodies, indicating their role as a promising tumor immunotherapy option. Immune checkpoints are also important in tumor immunotherapy. Programmed cell death protein-1 (PD-1) is a widely acknowledged immune checkpoint target with effective anti-tumor ac

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… These redirected cytotoxic T cells then release perforin/granzyme B to eliminate the tumor cells [ 29 ]. Blinatumomab was initially developed for Philadelphia chromosome-negative patients with R/R B-ALL. …

Harnessing the potential of CAR-T cell therapy: progress, challenges, and future directions in hematological and solid tumor treatments.

Traditional cancer treatments use nonspecific drugs and monoclonal antibodies to target tumor cells. Chimeric antigen receptor (CAR)-T cell therapy, however, leverages the immune system's T-cells to recognize and attack tumor cells. T-cells are isolated from patients and modified to target tumor-associated antigens. CAR-T therapy has achieved FDA approval for treating blood cancers like B-cell acute lymphoblastic leukemia, large B-cell lymphoma, and multiple myeloma by targeting CD-19 and B-cell maturation antigens. Bi-specific chimeric antigen receptors may contribute to mitigating tumor anti

Immunomodulatory Nanosystems.

Immunotherapy has emerged as an effective strategy for the prevention and treatment of a variety of diseases, including cancer, infectious diseases, inflammatory diseases, and autoimmune diseases. Immunomodulatory nanosystems can readily improve the therapeutic effects and simultaneously overcome many obstacles facing the treatment method, such as inadequate immune stimulation, off-target side effects, and bioactivity loss of immune agents during circulation. In recent years, researchers have continuously developed nanomaterials with new structures, properties, and functions. This Review provi

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… CTLs recognized the antigens expressed on the surface of infected cells and initiated perforin‐mediated cytotoxicity, which led to membrane destruction of both HIV‐infected cells and LNCs, followed by the release of IL‐15 agonist. …