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International Journal of Molecular... Oct 2022Immune evasion and metabolic reprogramming are two fundamental hallmarks of cancer. Interestingly, lactate closely links them together. However, lactate has long been... (Review)
Review
Immune evasion and metabolic reprogramming are two fundamental hallmarks of cancer. Interestingly, lactate closely links them together. However, lactate has long been recognized as a metabolic waste product. Lactate and the acidification of the tumor microenvironment (TME) promote key carcinogenesis processes, including angiogenesis, invasion, metastasis, and immune escape. Notably, histone lysine lactylation (Kla) was identified as a novel post-modification (PTM), providing a new perspective on the mechanism by which lactate functions and providing a promising and potential therapy for tumors target. Further studies have confirmed that protein lactylation is essential for lactate to function; it involves important life activities such as glycolysis-related cell functions and macrophage polarization. This review systematically elucidates the role of lactate as an immunosuppressive molecule from the aspects of lactate metabolism and the effects of histone lysine or non-histone lactylation on immune cells; it provides new ideas for further understanding protein lactylation in elucidating lactate regulation of cell metabolism and immune function. We explored the possibility of targeting potential targets in lactate metabolism for cancer treatment. Finally, it is promising to propose a combined strategy inhibiting the glycolytic pathway and immunotherapy.
Topics: Histones; Humans; Immunologic Deficiency Syndromes; Immunosuppression Therapy; Lactic Acid; Lysine; Neoplasms; Tumor Microenvironment; Waste Products
PubMed: 36233246
DOI: 10.3390/ijms231911943 -
Blood Advances Jun 2021Establishing a diagnosis of aplastic anemia (AA) can be challenging, but it is absolutely critical to appropriate management, especially differentiating between acquired... (Review)
Review
Establishing a diagnosis of aplastic anemia (AA) can be challenging, but it is absolutely critical to appropriate management, especially differentiating between acquired and inherited forms of the disease. The hematology field requires updated diagnostic guidelines to ensure that appropriate clinical pathways are pursued for patients and their safety. There are increasing clinical options for patients with immunosuppressive therapy and transplant once the diagnosis is made. In a case-based format, this review emphasizes the newer data on molecular (somatic and germline) findings in AA and how they are (or are not) helpful during diagnosis. There are key details on somatic mutation profiles and stated evidence where available for prognostic and treatment indications. Germline details of newer syndromes are also outlined, which make this review modern and reflect areas of uncertainty for clinicians.
Topics: Anemia, Aplastic; Humans; Immunosuppression Therapy
PubMed: 34156438
DOI: 10.1182/bloodadvances.2021004345 -
Frontiers in Immunology 2022In cancer, neutrophils are an important part of the tumour microenvironment (TME). Previous studies have shown that circulating and infiltrating neutrophils are... (Review)
Review
In cancer, neutrophils are an important part of the tumour microenvironment (TME). Previous studies have shown that circulating and infiltrating neutrophils are associated with malignant progression and immunosuppression in gliomas. However, recent studies have shown that neutrophils have an antitumour effect. In this review, we focus on the functional roles of neutrophils in the circulation and tumour sites in patients with glioma. The mechanisms of neutrophil recruitment, immunosuppression and the differentiation of neutrophils are discussed. Finally, the potential of neutrophils as clinical biomarkers and therapeutic targets is highlighted. This review can help us gain a deeper and systematic understanding of the role of neutrophils, and provide new insights for treatment in gliomas.
Topics: Glioma; Humans; Immunosuppression Therapy; Neutrophil Infiltration; Neutrophils; Tumor Microenvironment
PubMed: 35860278
DOI: 10.3389/fimmu.2022.927233 -
EBioMedicine Dec 2022Sepsis is an ill-defined syndrome yet is a leading cause of morbidity and mortality worldwide. The most recent consensus defines sepsis as life-threatening organ... (Review)
Review
Sepsis is an ill-defined syndrome yet is a leading cause of morbidity and mortality worldwide. The most recent consensus defines sepsis as life-threatening organ dysfunction caused by a dysregulated host response to infection. However, this definition belies the complexity and breadth of immune mechanisms involved in sepsis, which are characterized by simultaneous hyperinflammation and immune suppression. In this review, we describe the immunopathogenesis of sepsis and highlight some recent pathophysiological findings that have expanded our understanding of sepsis. Sepsis endotypes can be used to divide sepsis patients in different groups with distinct immune profiles and outcomes. We also summarize evidence on the role of the gut microbiome in sepsis immunity. The challenge of the coming years will be to translate our increasing knowledge about the molecular mechanisms underlying sepsis into therapies that improve relevant patient outcomes.
Topics: Humans; Sepsis; Immunosuppression Therapy; Gastrointestinal Microbiome
PubMed: 36470832
DOI: 10.1016/j.ebiom.2022.104363 -
Clinical Journal of the American... Aug 2021The long-term management of maintenance immunosuppression in kidney transplant recipients remains complex. The vast majority of patients are treated with the calcineurin... (Review)
Review
The long-term management of maintenance immunosuppression in kidney transplant recipients remains complex. The vast majority of patients are treated with the calcineurin inhibitor tacrolimus as the primary agent in combination with mycophenolate, with or without corticosteroids. A tacrolimus trough target 5-8 ng/ml seems to be optimal for rejection prophylaxis, but long-term tacrolimus-related side effects and nephrotoxicity support the ongoing evaluation of noncalcineurin inhibitor-based regimens. Current alternatives include belatacept or mammalian target of rapamycin inhibitors. For the former, superior kidney function at 7 years post-transplant compared with cyclosporin generated initial enthusiasm, but utilization has been hampered by high initial rejection rates. Mammalian target of rapamycin inhibitors have yielded mixed results as well, with improved kidney function tempered by higher risk of rejection, proteinuria, and adverse effects leading to higher discontinuation rates. Mammalian target of rapamycin inhibitors may play a role in the secondary prevention of squamous cell skin cancer as conversion from a calcineurin inhibitor to an mammalian target of rapamycin inhibitor resulted in a reduction of new lesion development. Early withdrawal of corticosteroids remains an attractive strategy but also is associated with a higher risk of rejection despite no difference in 5-year patient or graft survival. A major barrier to long-term graft survival is chronic alloimmunity, and regardless of agent used, managing the toxicities of immunosuppression against the risk of chronic antibody-mediated rejection remains a fragile balance.
Topics: Abatacept; Adrenal Cortex Hormones; Calcineurin Inhibitors; Drug Therapy, Combination; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; MTOR Inhibitors; Maintenance Chemotherapy; Mycophenolic Acid; Tacrolimus; Time Factors
PubMed: 33853841
DOI: 10.2215/CJN.15040920 -
Frontiers in Immunology 2023As critical executors regulating many cellular operations, proteins determine whether living activities can be performed in an orderly and efficient manner. Precursor... (Review)
Review
As critical executors regulating many cellular operations, proteins determine whether living activities can be performed in an orderly and efficient manner. Precursor proteins are inert and must be modified posttranslationally to enable a wide range of protein types and functions. Protein posttranslational modifications (PTMs) are well recognized as being directly associated with carcinogenesis and immune modulation and have emerged as important targets for cancer detection and treatment. Lactylation (Kla), a novel PTM associated with cellular metabolism found in a wide range of cells, interacts with both histone and nonhistone proteins. Unlike other epigenetic changes, Kla has been linked to poor tumor prognosis in all current studies. Histone Kla can affect gene expression in tumors and immunological cells, thereby promoting malignancy and immunosuppression. Nonhistone proteins can also regulate tumor progression and treatment resistance through Kla. In this review, we aimed to summarize the role of Kla in the onset and progression of cancers, metabolic reprogramming, immunosuppression, and intestinal flora regulation to identify new molecular targets for cancer therapy and provide a new direction for combined targeted therapy and immunotherapy.
Topics: Humans; Histones; Immunosuppression Therapy; Carcinogenesis; Immunotherapy; Epigenesis, Genetic
PubMed: 37646027
DOI: 10.3389/fimmu.2023.1253064 -
Cytokine & Growth Factor Reviews Feb 2023Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. In sepsis, a complicated immune response is initiated, which varies... (Review)
Review
Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. In sepsis, a complicated immune response is initiated, which varies over time with sustained excessive inflammation and immunosuppression. Identifying a promising way to orchestrate sepsis-induced immunosuppression is a challenge. Myeloid-derived suppressor cells (MDSCs) comprise pathologically activated neutrophils and monocytes with potent immunosuppressive activity. They play an important part in inhibiting innate and adaptive immune responses, and have emerged as part of the immune response in sepsis. MDSCs numbers are persistently high in sepsis patients, and associated with nosocomial infections and other adverse clinical outcomes. However, their characteristics and functional mechanisms during sepsis have not been addressed fully. Our review sheds light on the features and suppressive mechanism of MDSCs. We also review the potential applications of MDSCs as biomarkers and targets for clinical treatment of sepsis.
Topics: Humans; Myeloid-Derived Suppressor Cells; Sepsis; Immunosuppression Therapy; Immune Tolerance; Monocytes
PubMed: 35927154
DOI: 10.1016/j.cytogfr.2022.07.007 -
Frontiers in Endocrinology 2022The Warburg effect, one of the hallmarks of tumors, produces large amounts of lactate and generates an acidic tumor microenvironment using glucose for glycolysis. As a... (Review)
Review
The Warburg effect, one of the hallmarks of tumors, produces large amounts of lactate and generates an acidic tumor microenvironment using glucose for glycolysis. As a metabolite, lactate not only serves as a substrate to provide energy for supporting cell growth and development but also acts as an important signal molecule to affect the biochemical functions of intracellular proteins and regulate the biological functions of different kinds of cells. Notably, histone lysine lactylation (Kla) is identified as a novel post-modification and carcinogenic signal, which provides the promising and potential therapeutic targets for tumors. Therefore, the metabolism and functional mechanism of lactate are becoming one of the hot fields in tumor research. Here, we review the production of lactate and its regulation on immunosuppressive cells, as well as the important role of Kla in hepatocellular carcinoma. Lactate and Kla supplement the knowledge gap in oncology and pave the way for exploring the mechanism of oncogenesis and therapeutic targets. Research is still needed in this field.
Topics: Carcinoma, Hepatocellular; Glycolysis; Humans; Immunosuppression Therapy; Lactic Acid; Liver Neoplasms; Tumor Microenvironment
PubMed: 35757394
DOI: 10.3389/fendo.2022.901495 -
Cells Jun 2022Exosomes are membranous structures secreted by nearly all cell types. As critical messengers for intercellular communication, exosomes deliver bioactive cargoes to... (Review)
Review
Exosomes are membranous structures secreted by nearly all cell types. As critical messengers for intercellular communication, exosomes deliver bioactive cargoes to recipient cells and are involved in multiple physiopathological processes, including immunoregulation. Our pioneering study revealed that cancer cells release programmed death-ligand 1-positive exosomes into the circulation to counter antitumor immunity systemically via T cells. Tumor cell-derived exosomes (TDEs) also play an immunosuppressive role in other immunocytes, including dendritic cells (DCs), macrophages, natural killer (NK) cells, and myeloid-derived suppressor cells (MDSCs). Moreover, exosomes secreted by nontumor cells in the tumor microenvironments (TMEs) also exert immunosuppressive effects. This review systematically provides a summary of the immunosuppression induced by exosomes in tumor microenvironments, which modulates tumor growth, invasion, metastasis, and immunotherapeutic resistance. Additionally, therapeutic strategies targeting the molecular mechanism of exosome-mediated tumor development, which may help overcome several obstacles, such as immune tolerance in oncotherapy, are also discussed. Detailed knowledge of the specific functions of exosomes in antitumor immunity may contribute to the development of innovative treatments.
Topics: Exosomes; Humans; Immune Tolerance; Immunosuppression Therapy; Neoplasms; Tumor Microenvironment
PubMed: 35741075
DOI: 10.3390/cells11121946 -
Military Medical Research Dec 2022Emerged evidence has indicated that immunosuppression is involved in the occurrence and development of sepsis. To provide clinical practice recommendations on the immune...
Emerged evidence has indicated that immunosuppression is involved in the occurrence and development of sepsis. To provide clinical practice recommendations on the immune function in sepsis, an expert consensus focusing on the monitoring and treatment of sepsis-induced immunosuppression was developed. Literature related to the immune monitoring and treatment of sepsis were retrieved from PubMed, Web of Science, and Chinese National Knowledge Infrastructure to design items and expert opinions were collected through an online questionnaire. Then, the Delphi method was used to form consensus opinions, and RAND appropriateness method was developed to provide consistency evaluation and recommendation levels for consensus opinions. This consensus achieved satisfactory results through two rounds of questionnaire survey, with 2 statements rated as perfect consistency, 13 as very good consistency, and 9 as good consistency. After summarizing the results, a total of 14 strong recommended opinions, 8 weak recommended opinions and 2 non-recommended opinions were produced. Finally, a face-to-face discussion of the consensus opinions was performed through an online meeting, and all judges unanimously agreed on the content of this consensus. In summary, this expert consensus provides a preliminary guidance for the monitoring and treatment of immunosuppression in patients with sepsis.
Topics: Humans; Consensus; Immunosuppression Therapy; Delphi Technique; Surveys and Questionnaires; Sepsis
PubMed: 36567402
DOI: 10.1186/s40779-022-00430-y