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Pediatric Transplantation Dec 2023The overarching goal in the care of pediatric liver transplant recipients is to optimize allograft and patient health. Balancing immunosuppression to maintain allograft... (Review)
Review
The overarching goal in the care of pediatric liver transplant recipients is to optimize allograft and patient health. Balancing immunosuppression to maintain allograft health while avoiding medication side effects is essential for long-term survival and optimal quality of life in pediatric liver transplant recipients. Utilizing precision medicine to personalize immunosuppression, which includes minimization and withdrawal, is core to this effort. The unique anatomy and physiology of the liver make it more tolerant to immune-mediated injury and a more favorable organ for immunosuppression minimization and withdrawal. However, several challenges exist. Standard biochemical values and histologic features may not reliably predict allograft health after a reduction in immunosuppression. Additionally, biochemical values alone do not reliably identify which patients can successfully develop operational tolerance, as there may be occult allograft injury despite normal liver enzymes. Finally, the durability of tolerance after successful reduction in immunosuppression remains uncertain over time. Innovative tools show promise in circumventing these challenges, but more research is needed to determine actual clinical utility. While immunosuppression-free transplant may not be a current reality for most pediatric liver transplant recipients, strategies to safely minimize immunosuppression without compromising allograft health are within reach. Each liver allograft and recipient pair requires a different degree of immune modulation, and through a structured process of minimization and withdrawal, immunosuppression can indeed be tailored in a precise, personalized way to optimize outcomes. This review focuses on the progress that has been made to individualize immunosuppression in pediatric liver transplantation to ensure optimal allograft and recipient health.
Topics: Humans; Child; Liver Transplantation; Immunosuppressive Agents; Quality of Life; Immunosuppression Therapy; Immune Tolerance; Graft Rejection; Transplantation Tolerance
PubMed: 37439035
DOI: 10.1111/petr.14575 -
Immunological Reviews Sep 2023The broad application of immune checkpoint inhibitors (ICIs) has led to significant gains in cancer outcomes. By abrogating inhibitory signals, ICIs promote T cell... (Review)
Review
The broad application of immune checkpoint inhibitors (ICIs) has led to significant gains in cancer outcomes. By abrogating inhibitory signals, ICIs promote T cell targeting of cancer cells but can frequently trigger autoimmune manifestations, termed immune-related adverse events (irAEs), affecting essentially any organ system. Among cardiovascular irAEs, immune-related myocarditis (irMyocarditis) is the most described and carries the highest morbidity. The currently recommended treatment for irMyocarditis is potent immunosuppression with corticosteroids and other agents, but this has limited evidence basis. The cellular pathophysiology of irMyocarditis remains poorly understood, though mouse models and human data have both implicated effector CD8 T cells, some of which are specific for the cardiomyocyte protein α-myosin. While the driving molecular signals and transcriptional programs are not well defined, the involvement of chemokine receptors such as CCR5 and CXCR3 has been proposed. Fundamental questions regarding why only approximately 1% of ICI recipients develop irMyocarditis and why irMyocarditis carries a much worse prognosis than other forms of lymphocytic myocarditis remain unanswered. Further work in both murine systems and with human samples are needed to identify better tools for diagnosis, risk-stratification, and treatment.
Topics: Humans; Animals; Mice; Myocarditis; Immune Checkpoint Inhibitors; CD8-Positive T-Lymphocytes; Neoplasms; Immunosuppression Therapy
PubMed: 37449556
DOI: 10.1111/imr.13240 -
The European Journal of Neuroscience Dec 2023Stroke is a leading cause of mortality and disability. It occurs when cerebral blood flow is disrupted via vascular occlusion or rupture, causing tissue damage. Research... (Review)
Review
Stroke is a leading cause of mortality and disability. It occurs when cerebral blood flow is disrupted via vascular occlusion or rupture, causing tissue damage. Research has extensively examined the role of the immune response in stroke pathophysiology, focusing on infiltrated immune cells and inflammatory molecules. However, the stroke's impact on immune physiology remains underexplored. While initially stroke triggers the activation of peripheral inflammation, a subsequent profound immunosuppression occurs in a matter of hours/days. This response, potentially shielding the brain from excessive inflammation, significantly affects stroke patients. Beyond rendering patients more susceptible to infections, immunosuppression generates diverse consequences by disrupting immune system functions that are crucial for organ homeostasis. This review explores the effects of immunosuppression on stroke patients, shedding light on potential issues in immune organs such as the spleen and bone marrow, as well as non-immune organs like the small intestine, liver and heart. By synthesizing existing literature and offering additional insights, this manuscript highlights the multifaceted impact of post-stroke immunosuppression.
Topics: Humans; Stroke; Brain; Immunosuppression Therapy; Immune System; Inflammation
PubMed: 37857561
DOI: 10.1111/ejn.16174 -
EMBO Reports Aug 2023Sepsis is a leading cause of in-hospital mortality resulting from a dysregulated response to infection. Novel immunomodulatory therapies targeting macrophage metabolism...
Sepsis is a leading cause of in-hospital mortality resulting from a dysregulated response to infection. Novel immunomodulatory therapies targeting macrophage metabolism have emerged as an important focus for current sepsis research. However, understanding the mechanisms underlying macrophage metabolic reprogramming and how they impact immune response requires further investigation. Here, we identify macrophage-expressed Spinster homolog 2 (Spns2), a major transporter of sphingosine-1-phosphate (S1P), as a crucial metabolic mediator that regulates inflammation through the lactate-reactive oxygen species (ROS) axis. Spns2 deficiency in macrophages significantly enhances glycolysis, thereby increasing intracellular lactate production. As a key effector, intracellular lactate promotes pro-inflammatory response by increasing ROS generation. The overactivity of the lactate-ROS axis drives lethal hyperinflammation during the early phase of sepsis. Furthermore, diminished Spns2/S1P signaling impairs the ability of macrophages to sustain an antibacterial response, leading to significant innate immunosuppression in the late stage of infection. Notably, reinforcing Spns2/S1P signaling contributes to balancing the immune response during sepsis, preventing both early hyperinflammation and later immunosuppression, making it a promising therapeutic target for sepsis.
Topics: Humans; Anion Transport Proteins; Immunosuppression Therapy; Lactates; Macrophages; Reactive Oxygen Species; Sepsis
PubMed: 37358015
DOI: 10.15252/embr.202256635 -
Frontiers in Cellular and Infection... 2023The in-depth studies reveal the interaction between the host and commensal microbiomes. Symbiotic bacteria influence in tumor initiation, progression, and response to... (Review)
Review
The in-depth studies reveal the interaction between the host and commensal microbiomes. Symbiotic bacteria influence in tumor initiation, progression, and response to treatment. Recently, intratumor bacteria have been a burgeoning research field. The tumor microenvironment is under vascular hyperplasia, aerobic glycolysis, hypoxia, and immunosuppression. It might be attractive for bacterial growth and proliferation. As a component of the tumor microenvironment, intratumor bacteria influence tumor growth and metastasis, as well as the efficacy of anti-tumor therapies. Therefore, understanding the intricate interplay of intratumoral bacteria and the host might contribute to better approaches to treat tumors. In this review, we summarize current evidence about roles of intratumor bacteria in tumor initiation and anti-tumor therapy, and what is remained to be solved in this field.
Topics: Humans; Neoplasms; Immunosuppression Therapy; Bacteria; Tumor Microenvironment
PubMed: 38235490
DOI: 10.3389/fcimb.2023.1273254 -
International Journal of Oral Science Jan 2024Tumor progression is closely related to tumor tissue metabolism and reshaping of the microenvironment. Oral squamous cell carcinoma (OSCC), a representative hypoxic...
Spatial transcriptomics reveals that metabolic characteristics define the tumor immunosuppression microenvironment via iCAF transformation in oral squamous cell carcinoma.
Tumor progression is closely related to tumor tissue metabolism and reshaping of the microenvironment. Oral squamous cell carcinoma (OSCC), a representative hypoxic tumor, has a heterogeneous internal metabolic environment. To clarify the relationship between different metabolic regions and the tumor immune microenvironment (TME) in OSCC, Single cell (SC) and spatial transcriptomics (ST) sequencing of OSCC tissues were performed. The proportion of TME in the ST data was obtained through SPOTlight deconvolution using SC and GSE103322 data. The metabolic activity of each spot was calculated using scMetabolism, and k-means clustering was used to classify all spots into hyper-, normal-, or hypometabolic regions. CD4T cell infiltration and TGF-β expression is higher in the hypermetabolic regions than in the others. Through CellPhoneDB and NicheNet cell-cell communication analysis, it was found that in the hypermetabolic region, fibroblasts can utilize the lactate produced by glycolysis of epithelial cells to transform into inflammatory cancer-associated fibroblasts (iCAFs), and the increased expression of HIF1A in iCAFs promotes the transcriptional expression of CXCL12. The secretion of CXCL12 recruits regulatory T cells (Tregs), leading to Treg infiltration and increased TGF-β secretion in the microenvironment and promotes the formation of a tumor immunosuppressive microenvironment. This study delineates the coordinate work axis of epithelial cells-iCAFs-Tregs in OSCC using SC, ST and TCGA bulk data, and highlights potential targets for therapy.
Topics: Humans; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck; Mouth Neoplasms; Immunosuppression Therapy; Transforming Growth Factor beta; Head and Neck Neoplasms; Gene Expression Profiling; Tumor Microenvironment
PubMed: 38287007
DOI: 10.1038/s41368-023-00267-8 -
The Journal of Clinical Investigation Dec 2023Foxp3-expressing Tregs employ multiple suppressive mechanisms to curtail conventional T cell (Tconv) responses and establish tissue homeostasis. How Foxp3 coordinates...
Foxp3-expressing Tregs employ multiple suppressive mechanisms to curtail conventional T cell (Tconv) responses and establish tissue homeostasis. How Foxp3 coordinates Treg contact-dependent suppressive function is not fully resolved. In this issue of the JCI, Wang and colleagues revealed that Foxp3-mediated inhibition of ryanodine receptor 2 (RyR2) led to strong Treg-DC interactions and enhanced immunosuppression. RyR2 depletion in Tconvs phenocopied this effect and equipped Tconvs with Treg-like suppressive function in multiple inflammatory or autoimmune contexts. This study provides molecular and therapeutic insights underlying how cell-cell contact limits immune reactivity.
Topics: Mice; Animals; T-Lymphocytes, Regulatory; Ryanodine Receptor Calcium Release Channel; Mice, Inbred C57BL; Immunosuppression Therapy; Forkhead Transcription Factors
PubMed: 38099491
DOI: 10.1172/JCI172986 -
Journal of the Egyptian National Cancer... Aug 2023Hypoxia arises due to insufficient oxygen delivery to rapidly proliferating tumour cells that outpace the available blood supply. It is a characteristic feature of most... (Review)
Review
Hypoxia arises due to insufficient oxygen delivery to rapidly proliferating tumour cells that outpace the available blood supply. It is a characteristic feature of most solid tumour microenvironments and plays a critical role in regulating anti-tumour immunity, enhancing tumoral heterogeneity, and promoting therapeutic resistance and poor clinical outcomes. Hypoxia-inducible factors (HIFs) are the major hypoxia-responsive transcription factors that are activated under low oxygenation conditions and have been identified to drive multifunctional roles in tumour immune evasion. The HIF signalling network serves as an attractive target for targeted therapeutic approaches. This review aims to provide a comprehensive overview of the most crucial mechanisms by which HIF controls the expression of immunosuppressive molecules and immune checkpoints, disrupts cancer immunogenicity, and induces immunotherapeutic resistance.
Topics: Humans; Tumor Microenvironment; Immunosuppression Therapy; Transcription Factors; Hypoxia; Signal Transduction
PubMed: 37646847
DOI: 10.1186/s43046-023-00186-z -
Cell Death & Disease Sep 2023Immunotherapy is considered a major breakthrough in the treatment of small cell lung cancer (SCLC), although its anti-tumor efficacy is limited. With a high degree of...
Immunotherapy is considered a major breakthrough in the treatment of small cell lung cancer (SCLC), although its anti-tumor efficacy is limited. With a high degree of malignancy and high heterogeneity, SCLC is difficult to treat in the clinic. A new combination strategy is urgently needed to further improve the efficacy of immunotherapy in patients with SCLC. By immunofluorescence, 100 SCLC patients in a local cohort were classified into the SCLC-A (high ASCL1 expression; n = 36), SCLC-N (high NEUROD1 expression; n = 32), SCLC-P (high POU2F3 expression; n = 14), and SCLC-Y (high YAP1 expression; n = 18) subtypes. Each SCLC molecular subtype represented different prognoses, tumor microenvironment traits, and immunotherapy sensitivities. Analysis of both the local and public cohorts suggested that the SCLC-Y subtype exhibited the worst clinical outcome (p < 0.05) when compared with other subtypes. SCLC with high YAP1 expression was characterized by high PD-L1 expression, high stromal score, T-cell functional impairment, and a close relationship with immune-related pathways. YAP1 upregulated PD-L1 expression and suppressed T cell activation, thus leading to immune evasion. In in vitro experiments, blockade of YAP1 promoted cancer cell apoptosis, immune cell proliferation, T-cell activation, and cytotoxic T-cell infiltration, thus further potentiating the efficacy of immunotherapy in patients with the SCLC-Y subtype.
Topics: Humans; Small Cell Lung Carcinoma; B7-H1 Antigen; Immunosuppression Therapy; Immunotherapy; Lung Neoplasms; Tumor Microenvironment
PubMed: 37752152
DOI: 10.1038/s41419-023-06053-y -
Frontiers in Immunology 2023Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies. It is characterized by a complex and immunosuppressive tumor microenvironment (TME), which... (Review)
Review
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies. It is characterized by a complex and immunosuppressive tumor microenvironment (TME), which is primarily composed of tumor cells, stromal cells, immune cells, and acellular components. The cross-interactions and -regulations among various cell types in the TME have been recognized to profoundly shape the immunosuppression features that meaningfully affect PDAC biology and treatment outcomes. In this review, we first summarize five cellular composition modules by integrating the cellular (sub)types, phenotypes, and functions in PDAC TME. Then we discuss an integrated overview of the cross-module regulations as a determinant of the immunosuppressive TME in PDAC. We also briefly highlight TME-targeted strategies that potentially improve PDAC therapy.
Topics: Humans; Tumor Microenvironment; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Immunosuppression Therapy
PubMed: 37771596
DOI: 10.3389/fimmu.2023.1258538