The potential for immune checkpoint modulators in cerebrovascular injury and inflammation

Kim, Jennifer E.; Patel, Kisha; Jackson, Christopher M.

doi:10.1080/14728222.2021.1869213

Cited by 16 publications

(16 citation statements)

References 164 publications

(122 reference statements)

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“…Recently, the inflammatory immune response has been shown to participate in all stages of the pathological progression of IS, including the production of inflammatory mediators and the chemotaxis of immune cells ( 5 ). After IS, an insufficient blood supply deprives brain cells of glucose and oxygen and disrupts the homeostasis of cells, thereby triggering pathophysiological processes, including excitotoxicity, oxidative stress, inflammation, apoptosis and cell death ( 1 ).…”

Section: Introductionmentioning

confidence: 99%

Comprehensive Landscape of Immune Infiltration and Aberrant Pathway Activation in Ischemic Stroke

Liu

Song

et al. 2022

Front. Immunol.

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Ischemic stroke (IS) is a multifactorial disease caused by the interaction of multiple environmental and genetic risk factors, and it is the most common cause of disability. The immune microenvironment and inflammatory response participate in the whole process of IS occurrence and development. Therefore, the rational use of relevant markers or characteristic pathways in the immune microenvironment will become one of the important therapeutic strategies for the treatment of IS. We collected peripheral blood samples from 10 patients diagnosed with IS at the First Affiliated Hospital of Gannan Medical University and First Affiliated Hospital, Jinan" University, and from 10 normal people. The GSE16561 dataset was downloaded from the Gene Expression Omnibus (GEO) database. xCell, gene set enrichment analysis (GSEA), single-sample GSEA (ssGSEA) and immune-related gene analysis were used to evaluate the differences in the immune microenvironment and characteristic pathways between the IS and control groups of the two datasets. xCell analysis showed that the IS-24h group had significantly reduced central memory CD8+ T cell, effector memory CD8+ T cell, B cell and Th1 cell scores and significantly increased M1 macrophage and macrophage scores. GSEA showed that the IS-24h group had significantly increased inflammation-related pathway activity(myeloid leukocyte activation, positive regulation of tumor necrosis factor biosynthetic process, myeloid leukocyte migration and leukocyte chemotaxis), platelet-related pathway activity(platelet activation, signaling and aggregation; protein polymerization; platelet degranulation; cell-cell contact zone) and pathology-related pathway activity (ERBB signaling pathway, positive regulation of ERK1 and ERK2 cascade, vascular endothelial growth factor receptor signaling pathway, and regulation of MAP kinase activity). Immune-related signature analysis showed that the macrophage signature, antigen presentation-related signature, cytotoxicity-related signature, B cell-related signature and inflammation-related signature were significantly lower in the IS-24h group than in the control group. In this study, we found that there were significant differences in the immune microenvironment between the peripheral blood of IS patients and control patients, as shown by the IS group having significantly reduced CD8+ Tcm, CD8+ Tem, B cell and Th1 cell scores and significantly increased macrophage and M1 macrophage scores. Additionally, inflammation-related, pathological, and platelet-related pathway activities were significantly higher in the IS group than in the control group.

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Section: Introductionmentioning

confidence: 99%

Comprehensive Landscape of Immune Infiltration and Aberrant Pathway Activation in Ischemic Stroke

Liu

Song

et al. 2022

Front. Immunol.

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“…Data from a variety of studies demonstrate that post-injury inflammation (such as that seen following ischaemia and/or trauma) is associated with high levels of activated T cells and high levels of immune-checkpoint expression 186 . However, functional studies differ regarding whether PD-1–PD-L1 inhibition or gene knockout is either protective 187 or detrimental in this setting 188 .…”

Section: Effects On Other Immune Processesmentioning

confidence: 99%

Immune-checkpoint inhibitors: long-term implications of toxicity

et al. 2022

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The development of immune-checkpoint inhibitors (ICIs) has heralded a new era in cancer treatment, enabling the possibility of long-term survival in patients with metastatic disease, and providing new therapeutic indications in earlier-stage settings. As such, characterizing the long-term implications of receiving ICIs has grown in importance. An abundance of evidence exists describing the acute clinical toxicities of these agents, although chronic effects have not been as well catalogued. Nonetheless, emerging evidence indicates that persistent toxicities might be more common than initially suggested. While generally low-grade, these chronic sequelae can affect the endocrine, rheumatological, pulmonary, neurological and other organ systems. Fatal toxicities also comprise a diverse set of clinical manifestations and can occur in 0.4–1.2% of patients. This risk is a particularly relevant consideration in light of the possibility of long-term survival. Finally, the effects of immune-checkpoint blockade on a diverse range of immune processes, including atherosclerosis, heart failure, neuroinflammation, obesity and hypertension, have not been characterized but remain an important area of research with potential relevance to cancer survivors. In this Review, we describe the current evidence for chronic immune toxicities and the long-term implications of these effects for patients receiving ICIs.

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“…67 Additionally, recent work has suggested the possibility of using immune checkpoint blockades as a potential drug target for limiting neuroinflammation following TBI or other neurological insults. 68 However, attempts to treat neurotrauma with anti-inflammatory agents have generally yielded poor results. 69 For example, the 6-month outcome results from the Corticosteroid Randomization After Significant Head Injury (CRASH) Trial showed that patients who were treated with corticosteroids after TBI had a higher risk of death or severe disability than patients who were treated with placebo.…”

Section: Is There An Adaptive Role Of Postinjury Immune Suppression?mentioning

confidence: 99%

Central nervous system injury–induced immune suppression

Sribnick

Popovich

Hall

2022

Neurosurgical Focus

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Central nervous system trauma is a common cause of morbidity and mortality. Additionally, these injuries frequently occur in younger individuals, leading to lifetime expenses for patients and caregivers and the loss of opportunity for society. Despite this prevalence and multiple attempts to design a neuroprotectant, clinical trials for a pharmacological agent for the treatment of traumatic brain injury (TBI) or spinal cord injury (SCI) have provided disappointing results. Improvements in outcome from these disease processes in the past decades have been largely due to improvements in supportive care. Among the many challenges facing patients and caregivers following neurotrauma, posttraumatic nosocomial infection is a significant and potentially reversible risk factor. Multiple animal and clinical studies have provided evidence of posttraumatic systemic immune suppression, and injuries involving the CNS may be even more prone, leading to a higher risk for in-hospital infections following neurotrauma. Patients who have experienced neurotrauma with nosocomial infection have poorer recovery and higher risks of long-term morbidity and in-hospital mortality than patients without infection. As such, the etiology and reversal of postneurotrauma immune suppression is an important topic. There are multiple possible etiologies for these posttraumatic changes including the release of damage-associated molecular patterns, the activation of immunosuppressive myeloid-derived suppressor cells, and sympathetic nervous system activation. Postinjury systemic immunosuppression, particularly following neurotrauma, provides a challenge for clinicians but also an opportunity for improvement in outcome. In this review, the authors sought to outline the evidence of postinjury systemic immune suppression in both animal models and clinical research of TBI, TBI polytrauma, and SCI.

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The potential for immune checkpoint modulators in cerebrovascular injury and inflammation

Cited by 16 publications

References 164 publications

Comprehensive Landscape of Immune Infiltration and Aberrant Pathway Activation in Ischemic Stroke

Comprehensive Landscape of Immune Infiltration and Aberrant Pathway Activation in Ischemic Stroke

Immune-checkpoint inhibitors: long-term implications of toxicity

Central nervous system injury–induced immune suppression

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