EDA-E7 Activated DCs Induces Cytotoxic T Lymphocyte Immune Responses against HPV Expressing Cervical Cancer in Human Setting
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Cervical cancer is a major cause of cancer death in women worldwide. Targeting human papillomavirus (HPV) viral oncoproteins E6 and E7 is a new strategy for cervical cancer immunotherapy and has been associated with resolution of HPV-induced lesions. How to efficiently induce T cell target killing of HPV infected cervical cancer is of great potential benefit for cervical cancer treatment. Fusion protein containing the extra domain A (EDA) from fibronectin, a natural ligand for Toll-like receptor 4 (TLR4), and HPVE7 (EDA-E7) has been shown to efficiently induce dendritic cells maturation and trigger specific antitumor CD8+ T cells response in mice. In this study, we constructed EDA-E7 fusion protein of human origin and tested its function in dendritic cell maturation as well as antitumor T cell response. We found that EDA-E7 could be efficiently captured by human PBMC derived dendritic cells (DCs) in vitro and induce DCs maturation. Importantly, this effect could work in synergy with the TLR ligand anti-CD40 agonist, polyinosinic-polycytidylic acid [poly (I:C)], R848, and CpG2216. EDA-E7 matured DCs could activate T cells and trigger an anti-tumor response in vitro. Single cell RNA sequencing and T cell targeted killing assay confirmed the activation of T cells by EDA-E7 matured DCs. Therefore, therapeutic vaccination with EDA-E7 fusion protein maybe effective for human cervical carcinoma treatment.Keywords:
Cancer Immunotherapy
Immunotherapy is a type of cancer treatment that works by harnessing the power of the immunesystem to recognize and attack cancer cells. Unlike traditional cancer treatments likechemotherapy and radiation therapy, which directly target cancer cells, immunotherapy aims toboost the body's natural defenses against cancer. The immune system is a complex network ofcells, tissues, and organs that work together to protect the body against harmful invaders likeviruses, bacteria, and cancer cells. Normally, the immune system is able to recognize and destroycancer cells as they develop, but sometimes cancer cells can evade detection and continue togrow and spread. Immunotherapy works by stimulating the immune system to recognize andattack cancer cells more effectively.
Cancer Immunotherapy
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The idea of exploiting the immune system to treat tumors (cancer immunotherapy) is at least a century old. Immunotherapy is generally classified into two functional approaches: Passive immunotherapy administers preformed elements of the immune system (tumor-reactive antibodies, antitumor cytokines, or tumoricidal effector cells) to patients with the intent that these agents will directly attack the cancer cells. Active immunotherapy (including tumor vaccines and immunostimulatory cytokines) is intended to stimulate the patients' immune system to generate effective antitumor immunity. Both passive and active immunotherapies are integral parts of modern medical practice for problems as diverse as the treatment of snakebites and the prevention of infectious diseases. Yet, for cancer, the role of the immune system and immunotherapy has been a topic of spirited debate for the last 50 years (1). Major points of contention have been whether tumor cells are immunogenic in their host of origin and whether the immune system is capable of controlling or eradicating malignant cells.
Cancer Immunotherapy
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Recent advances in immunology have greatly increased our understanding of immunological tolerance. In particular, there has been a resurgence of interest in mechanisms of immune regulation. Immune regulation refers to the phenomenon, previously known as immune suppression, by which excessive responses to infectious agents and hypersensitivities to otherwise innocuous antigens such as self antigens and allergens are avoided. We now appreciate that various distinct cell types mediate immune suppression and that some of these may be induced by appropriate administration of antigens, synthetic peptides and drugs of various types. The induction of antigen specific immunotherapy for treatment of autoimmune and allergic diseases remains the holy grail for treatment of these diseases. This goal comes ever closer as understanding of the mechanisms of immune suppression and in particular antigen specific immunotherapy increases. Here we review evidence that immune suppression is mediated by various different subsets of CD4 T cells. Keywords: Autoimmunity, allergy, T-cell, cytokine, immune regulation, antigen, peptide
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Dendritic cells (DC) are the most potent antigen-presenting cells that initiate T cell-mediated immune responses. The development of methods to generate a large number of DC in vitro has facilitated their application to immunotherapy. Adding tumor antigens to DC in vitro and administering them to cancer patients is expected to induce effective immune responses to cancers, which are poorly immunogenic in most cases. There are several parameters that need to be optimized to improve the efficacy of DC-based immunotherapy. Because the immune system has developed in order to eliminate microbial pathogens and is thus well equipped with machinery for that purpose, reproducing events occurring during anti-infection immune responses for antitumor immunity may lead to the development of effective tumor immunotherapy.
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Cancer Immunotherapy
Biocompatibility
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Cancer immunotherapy has been intensively investigated in both preclinical and clinical studies. Whereas chemotherapies use cytotoxic drugs to kill tumor cells, cancer immunotherapy is based on the ability of the immune system to fight cancer. Tumors are intimately associated with the immune system: they can suppress the immune response and/or control immune cells to support tumor growth. Immunotherapy has yielded promising results in clinical practice, but some patients show limited responses. This may reflect the complexities of the relationship between a tumor and the immune system. In an effort to improve the current immunotherapies, researchers have exploited nanomaterials in creating new strategies to cure tumors via modulation of the immune system in tumor tissues. Although extensive studies have examined the use of immune checkpoint-based immunotherapy, rather less work has focused on manipulating the innate immune cells. This review examines the recent approaches and challenges in the use of nanomaterials to modulate innate immune cells.
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The principal role of the immune system is to prevent and eradicate pathogens and infections. The key characteristics or features of an effective immune response include specificity, trafficking, antigen spread and durability (memory). The immune system is recognised to have a critical role in controlling cancer through a dynamic relationship with tumour cells. Normally, at the early stages of tumour development, the immune system is capable of eliminating tumour cells or keeping tumour growth abated; however, tumour cells may evolve multiple pathways over time to evade immune control. Immunotherapy may be viewed as a treatment designed to boost or restore the ability of the immune system to fight cancer, infections and other diseases. Immunotherapy manifests differently from traditional cancer treatments, eliciting delayed response kinetics and thus may be more effective in patients with lower tumour burden, in whom disease progression may be less rapid, thereby allowing ample time for the immunotherapy to evolve. Because immunotherapies may have a different mechanism of action from traditional cytotoxic or targeted biological agents, immunotherapy techniques have the potential to combine synergistically with traditional therapies.
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Objective To evaluate the clinical application of autologous dendritic tumor vaccination on brain glioma, and to access the alterations of T cell subpopulation in patients with brain glioma before and after autologous immunotherapy. Methods The experimental group (21 Glioma patients) received vaccinations of autologous dendritic cell pulsed with autologous tumor peptides, while the control group (19 glioma patients) only received the regular treatments. Following-ups were carried out and the T cell subpopulations were measured. Results The median survival time of the experimental group (29 months) was significantly longer than that of control group (10 month) (P 0.05). The levels of CD3 + and CD4 + and the ratio of CD4 +/CD8 + ratio in peripheral blood in glioma patients were significantly lower compared with the healthy control, the levels of CD3 +, CD4 +, CD8 +and the CD4 +/CD8 + ratio were significantly increased after immunotherapy than before, but the CD4 +/CD8 + ratio remained lower compared with the healthy control. Conclusion The immune functions of glioma patients were suppressed. Immunotherapy could prolong the survival time of the glioma patient by reconstructing and enhancing some parts of the tumor immunity.
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Immunotherapy has demonstrated impressive outcomes for some patients with cancer. However, selecting patients who are most likely to respond to immunotherapy remains a clinical challenge. Here, we discuss immune escape mechanisms exploited by cancer and present strategies for applying this knowledge to improving the efficacy of cancer immunotherapy.
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Immune escape
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Successful immunotherapy for the treatment of cancer depends on multiple facets of immune cell biology, including the proper migration of immune cells that are involved in mounting the antitumor immune response. In this chapter, we describe an array of approaches that can be employed to modify immune cell migration for the enhancement of cancer immunotherapy. We divide these approaches into three categories: ex vivo modification of immune cell migration, immunotherapy at the tumor site to enhance immune cell migration, and systemic application of drugs and biologicals.
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