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Seminars in Cancer Biology Dec 2015Cancer immune evasion is a major stumbling block in designing effective anticancer therapeutic strategies. Although considerable progress has been made in understanding... (Review)
Review
Cancer immune evasion is a major stumbling block in designing effective anticancer therapeutic strategies. Although considerable progress has been made in understanding how cancers evade destructive immunity, measures to counteract tumor escape have not kept pace. There are a number of factors that contribute to tumor persistence despite having a normal host immune system. Immune editing is one of the key aspects why tumors evade surveillance causing the tumors to lie dormant in patients for years through "equilibrium" and "senescence" before re-emerging. In addition, tumors exploit several immunological processes such as targeting the regulatory T cell function or their secretions, antigen presentation, modifying the production of immune suppressive mediators, tolerance and immune deviation. Besides these, tumor heterogeneity and metastasis also play a critical role in tumor growth. A number of potential targets like promoting Th1, NK cell, γδ T cell responses, inhibiting Treg functionality, induction of IL-12, use of drugs including phytochemicals have been designed to counter tumor progression with much success. Some natural agents and phytochemicals merit further study. For example, use of certain key polysaccharide components from mushrooms and plants have shown to possess therapeutic impact on tumor-imposed genetic instability, anti-growth signaling, replicative immortality, dysregulated metabolism etc. In this review, we will discuss the advances made toward understanding the basis of cancer immune evasion and summarize the efficacy of various therapeutic measures and targets that have been developed or are being investigated to enhance tumor rejection.
Topics: Antigen Presentation; Carcinogenesis; Humans; Immune Evasion; Immune Tolerance; Neoplasms; Phytochemicals; T-Lymphocytes, Regulatory; Tumor Escape
PubMed: 25818339
DOI: 10.1016/j.semcancer.2015.03.004 -
Frontiers in Immunology 2022Tumor microenvironment is the general term for all non-cancer components and their metabolites in tumor tissue. These components include the extracellular matrix,... (Review)
Review
Tumor microenvironment is the general term for all non-cancer components and their metabolites in tumor tissue. These components include the extracellular matrix, fibroblasts, immune cells, and endothelial cells. In the early stages of tumors, the tumor microenvironment has a tumor suppressor function. As the tumor progresses, tumor immune tolerance is induced under the action of various factors, such that the tumor suppressor microenvironment is continuously transformed into a tumor-promoting microenvironment, which promotes tumor immune escape. Eventually, tumor cells manifest the characteristics of malignant proliferation, invasion, metastasis, and drug resistance. In recent years, stress effects of the extracellular matrix, metabolic and phenotypic changes of innate immune cells (such as neutrophils, mast cells), and adaptive immune cells in the tumor microenvironment have been revealed to mediate the emerging mechanisms of immune tolerance, providing us with a large number of emerging therapeutic targets to relieve tumor immune tolerance. Gastric cancer is one of the most common digestive tract malignancies worldwide, whose mortality rate remains high. According to latest guidelines, the first-line chemotherapy of advanced gastric cancer is the traditional platinum and fluorouracil therapy, while immunotherapy for gastric cancer is extremely limited, including only Human epidermal growth factor receptor 2 (HER-2) and programmed death ligand 1 (PD-L1) targeted drugs, whose benefits are limited. Clinical experiments confirmed that cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), vascular endothelial growth factor receptor (VEGFR) and other targeted drugs alone or in combination with other drugs have limited efficacy in patients with advanced gastric cancer, far less than in lung cancer, colon cancer, and other tumors. The failure of immunotherapy is mainly related to the induction of immune tolerance in the tumor microenvironment of gastric cancer. Therefore, solving the immune tolerance of tumors is key to the success of gastric cancer immunotherapy. In this study, we summarize the latest mechanisms of various components of the tumor microenvironment in gastric cancer for inducing immune tolerance and promoting the formation of the malignant phenotype of gastric cancer, as well as the research progress of targeting the tumor microenvironment to overcome immune tolerance in the treatment of gastric cancer.
Topics: Humans; Tumor Microenvironment; Stomach Neoplasms; Endothelial Cells; Vascular Endothelial Growth Factor A; Immune Tolerance
PubMed: 36341377
DOI: 10.3389/fimmu.2022.1016817 -
Nature Reviews. Immunology Mar 2012Myeloid cells are the most abundant nucleated haematopoietic cells in the human body and are a collection of distinct cell populations with many diverse functions. The... (Review)
Review
Myeloid cells are the most abundant nucleated haematopoietic cells in the human body and are a collection of distinct cell populations with many diverse functions. The three groups of terminally differentiated myeloid cells - macrophages, dendritic cells and granulocytes - are essential for the normal function of both the innate and adaptive immune systems. Mounting evidence indicates that the tumour microenvironment alters myeloid cells and can convert them into potent immunosuppressive cells. Here, we consider myeloid cells as an intricately connected, complex, single system and we focus on how tumours manipulate the myeloid system to evade the host immune response.
Topics: Animals; Antineoplastic Agents; Humans; Immune Tolerance; Myeloid Cells; Neoplasms
PubMed: 22437938
DOI: 10.1038/nri3175 -
Frontiers in Immunology 2018
Topics: Animals; Humans; Immune Tolerance; Metabolism
PubMed: 30498502
DOI: 10.3389/fimmu.2018.02678 -
Nature Communications Mar 2021Tyrosine kinase inhibitors were found to be clinically effective for treatment of patients with certain subsets of cancers carrying somatic mutations in receptor...
Tyrosine kinase inhibitors were found to be clinically effective for treatment of patients with certain subsets of cancers carrying somatic mutations in receptor tyrosine kinases. However, the duration of clinical response is often limited, and patients ultimately develop drug resistance. Here, we use single-cell RNA sequencing to demonstrate the existence of multiple cancer cell subpopulations within cell lines, xenograft tumors and patient tumors. These subpopulations exhibit epigenetic changes and differential therapeutic sensitivity. Recurrently overrepresented ontologies in genes that are differentially expressed between drug tolerant cell populations and drug sensitive cells include epithelial-to-mesenchymal transition, epithelium development, vesicle mediated transport, drug metabolism and cholesterol homeostasis. We show analysis of identified markers using the LINCS database to predict and functionally validate small molecules that target selected drug tolerant cell populations. In combination with EGFR inhibitors, crizotinib inhibits the emergence of a defined subset of EGFR inhibitor-tolerant clones. In this study, we describe the spectrum of changes associated with drug tolerance and inhibition of specific tolerant cell subpopulations with combination agents.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Cholesterol; Drug Combinations; Drug Discovery; Drug Resistance, Neoplasm; Drug Tolerance; Epithelial-Mesenchymal Transition; ErbB Receptors; Gene Expression Regulation, Neoplastic; Heterografts; Humans; Mutation; Neoplasms; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases; U937 Cells
PubMed: 33712615
DOI: 10.1038/s41467-021-21884-z -
Current Opinion in Organ Transplantation Oct 2020To describe the most recent progress towards tolerance in xenotransplantation. (Review)
Review
PURPOSE OF REVIEW
To describe the most recent progress towards tolerance in xenotransplantation.
RECENT FINDINGS
Mixed chimerism and thymic transplantation have been used to promote tolerance in xenotransplantation models. Intra-bone bone marrow transplantation is a recent advance for mixed chimerism, which promotes longer lasting chimerism and early graft function of subsequent organ transplantation. The hybrid thymus, an advancement to the vascularized thymokidney and vascularized thymic lobe, is being developed to allow for both donor and recipient T-cell selection in the chimeric thymus, encouraging tolerance to self and donor while maintaining appropriate immune function. Regulatory T cells show promise to promote tolerance by suppressing effector T cells and by supporting mixed chimerism. Monoclonal antibodies such as anti-CD2 may promote tolerance through suppression of CD2+ effector and memory T cells whereas Tregs, which express lower numbers of CD2, are relatively spared and might be used to promote tolerance.
SUMMARY
These findings contribute major advances to tolerance in xenotransplantation. A combination of many of these mechanisms will likely be needed to have long-term tolerance maintained without the use of immunosuppression.
Topics: Animals; Chimerism; Immune Tolerance; Models, Animal; Transplantation Tolerance; Transplantation, Heterologous
PubMed: 32796179
DOI: 10.1097/MOT.0000000000000795 -
Frontiers in Immunology 2022Food allergy is a growing concern due to its increasing world-wide incidence. Strict avoidance of allergens is a passive treatment strategy. Since the mechanisms... (Review)
Review
Food allergy is a growing concern due to its increasing world-wide incidence. Strict avoidance of allergens is a passive treatment strategy. Since the mechanisms responsible for the occurrence and development of food allergy have not yet been fully elucidated, effective individualized treatment options are lacking. In this review, we summarize the pathways through which food antigens enter the intestine and review the proposed mechanisms describing how the intestine acquires and tolerates food antigens. When oral tolerance is not established, food allergy occurs. In addition, we also discuss the contribution of commensal bacteria of the gut in shaping tolerance to food antigens in the intestinal tract. Finally, we propose that elucidating the mechanisms of intestinal uptake and tolerance of food antigens will provide additional clues for potential treatment options for food allergy.
Topics: Allergens; Antigens; Bacteria; Food; Food Hypersensitivity; Humans; Immune Tolerance
PubMed: 35757706
DOI: 10.3389/fimmu.2022.906122 -
Human Immunology May 2018Current theory holds that macrochimerism is essential to the development of transplant tolerance. Hematopoietic cell transplantation from the solid organ donor is... (Review)
Review
Current theory holds that macrochimerism is essential to the development of transplant tolerance. Hematopoietic cell transplantation from the solid organ donor is necessary to achieve macrochimerism. Over the last 10-20 years, trials of tolerance induction with combined kidney and hematopoietic cell transplantation have moved from the preclinical to the clinical arena. The achievement of macrochimerism in the clinical setting is challenging, and potentially toxic due to the conditioning regimen necessary to hematopoietic cell transplantation and due to the risk of graft-versus-host disease. There are differences in chimerism goals and methods of the three major clinical stage tolerance induction strategies in both HLA-matched and HLA-mismatched living donor kidney transplantation, with consequent differences in efficacy and safety. The Stanford protocol has proven efficacious in the induction of tolerance in HLA-matched kidney transplantation, allowing cessation of immunosuppressive drug therapy in 80% of study participants, with the safety profile of conventional transplantation. In HLA-mismatched transplantation, multi-lineage macrochimerism of over a year's duration can now be consistently achieved with the Stanford protocol, with complete withdrawal of immunosuppressive drug therapy during the second post-transplant year as the next experimental step and test of tolerance.
Topics: Chimerism; Clinical Protocols; Hematopoietic Stem Cell Transplantation; Histocompatibility Testing; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphatic Irradiation; Transplantation Chimera; Transplantation Conditioning; Transplantation Tolerance
PubMed: 29330112
DOI: 10.1016/j.humimm.2018.01.002 -
Journal of Immunology Research 2017Tumor necrosis factor (TNF) tolerance in monocytes and macrophages means that preexposure to TNF reduces the sensitivity in these cells to a subsequent restimulation... (Review)
Review
Tumor necrosis factor (TNF) tolerance in monocytes and macrophages means that preexposure to TNF reduces the sensitivity in these cells to a subsequent restimulation with this cytokine. Differential effects arise following preincubation with both low and high doses of TNF resulting in absolute as well as induction tolerance affecting specific immunologically relevant gene sets. In this review article, we summarize the relevance of TNF tolerance and the molecular mechanisms underlying these forms of tolerance including the role of transcription factors and signaling systems. In addition, the characteristics of cross-tolerance between TNF and lipopolysaccharide (LPS) as well as pathophysiological aspects of TNF tolerance are discussed. We conclude that TNF tolerance may represent a protective mechanism involved in the termination of inflammation and preventing excessive or prolonged inflammation. Otherwise, tolerance may also be a trigger of immune paralysis thus contributing to severe inflammatory diseases such as sepsis. An improved understanding of TNF tolerance will presumably facilitate the implementation of diagnostic or therapeutic approaches to more precisely assess and treat inflammation-related diseases.
Topics: Animals; Drug Tolerance; Gene Expression Regulation; Humans; Immune Tolerance; Inflammation; Lipopolysaccharides; Macrophages; Monocytes; Signal Transduction; Transcription Factors; Tumor Necrosis Factor-alpha
PubMed: 29250561
DOI: 10.1155/2017/9570129 -
American Journal of Transplantation :... Jul 2016Exhaustion of lymphocyte function through chronic exposure to a high load of foreign antigen is well established for chronic viral infection and antitumor immunity and... (Review)
Review
Exhaustion of lymphocyte function through chronic exposure to a high load of foreign antigen is well established for chronic viral infection and antitumor immunity and has been found to be associated with a distinct molecular program and characteristic cell surface phenotype. Although exhaustion has most commonly been studied in the context of CD8 viral responses, recent studies indicate that chronic antigen exposure may affect B cells, NK cells and CD4 T cells in a parallel manner. Limited information is available regarding the extent of lymphocyte exhaustion development in the transplant setting and its impact on anti-graft alloreactivity. By analogy to the persistence of a foreign virus, the large mass of alloantigen presented by an allograft in chronic residence could provide an ideal setting for exhausting donor-reactive T cells. The extent of T cell exhaustion occurring with various allografts, the kinetics of its development, whether exhaustion is influenced positively or negatively by different immunosuppressants, and the impact of exhaustion on graft survival and tolerance development remains a fertile area for investigation. Harnessing or encouraging the natural processes of exhaustion may provide a novel means to promote graft survival and transplantation tolerance.
Topics: Graft Rejection; Humans; Immune Tolerance; Organ Transplantation; Transplantation Tolerance
PubMed: 26729653
DOI: 10.1111/ajt.13702