Proteomic characterization of checkpoint inhibitor-induced liver injury
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ABSTRACT:
INSTRUMENT(S): Orbitrap Eclipse
ORGANISM(S): Homo Sapiens (ncbitaxon:9606)
SUBMITTER: 
Mireia Fernandez Ocana
PROVIDER: MSV000096928 | MassIVE | Fri Jan 24 07:01:00 GMT 2025
SECONDARY ACCESSION(S): PXD060159
REPOSITORIES: MassIVE
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Project description:Immune checkpoint inhibitors (ICI) targeting CTLA-4 and PD-1 have shown remarkable antitumor efficacy but can also cause immune-related adverse events, including checkpoint inhibitor-induced liver injury (ChILI). This multi-omic study aimed to investigate changes in blood samples from treated cancer patients who developed ChILI. PBMCs were analyzed by transcriptomic and T cell receptor sequencing (bulk and single cell), and extracellular vesicle (EV) enrichment from plasma was analyzed by mass spectroscopy proteomics. Data were analyzed by comparing the ChILI patient group to the control group who did not develop ChILI and by comparing the onset of ChILI to pre-ICI treatment baseline. We identified significant changes in T cell clonality, gene expression, and protein levels in peripheral blood mononuclear cells (PBMCs) or plasma at the time of liver injury. Onset of ChILI was accompanied by an increase in T-cell clonality. Pathway analysis highlighted the involvement of innate and cellular immune responses, mitosis, pyroptosis, and oxidative stress. Single-cell RNA sequencing revealed that these changes were primarily found in select T cell subtypes (including CD8+ effector memory cells), while CD16+ monocytes exhibited enrichment in metabolic pathways. Proteomic analysis of plasma extracellular vesicles showed enrichment in liver-associated proteins among differentially expressed proteins. Interestingly, an increase in PBMC PD-L1 gene expression and plasma PD-L1 protein was also found to be associated with onset of ChILI.
2025-01-22 | GSE287541 | GEO
Project description:Background & aimsImmune checkpoint inhibitors (ICIs) have changed the landscape of cancer therapy. Liver toxicity occurs in up to 25% of patients treated with ICIs. The aim of our study was to describe the different clinical patterns of ICI-induced hepatitis and to assess their outcome.MethodsWe conducted a retrospective observational study of patients with checkpoint inhibitor-induced liver injury (CHILI) discussed in multidisciplinary meetings between December 2018 and March 2022 in three French centres specialised in ICI toxicity management (Montpellier, Toulouse, Lyon). The hepatitis clinical pattern was analysed by the ratio of serum alanine aminotransferase (ALT) and alkaline phosphatase (ALP) (R value = (ALT/ULN)/(ALP/ULN)) for characterisation as cholestatic (R ≤2), hepatocellular (R ≥5), or mixed (2 <R <5).ResultsWe included 117 patients with CHILI. The clinical pattern was hepatocellular in 38.5%, cholestatic in 36.8%, and mixed in 24.8% of patients. High-grade hepatitis severity (grade ≥3 according to the Common Terminology Criteria for Adverse Events system) was significantly associated with the hepatocellular hepatitis (p <0.05). No cases of severe acute hepatitis were reported. Liver biopsy was performed in 41.9% of patients: granulomatous lesions, endothelitis, or lymphocytic cholangitis were described. Biliary stenosis occurred in eight patients (6.8%) and was significantly more frequent in the cholestatic clinical pattern (p < 0.001). Steroids alone were mainly administered to patients with a hepatocellular clinical pattern (26.5%), and ursodeoxycholic acid was more frequently used in the cholestatic pattern (19.7%) than in the hepatocellular or mixed clinical pattern (p <0.001). Seventeen patients improved without any treatment. Among the 51 patients (43.6%) rechallenged with ICIs, 12 (23.5%) developed CHILI recurrence.ConclusionsThis large cohort indicates the different clinical patterns of ICI-induced liver injury and highlights that the cholestatic and hepatocellular patterns are the most frequent with different outcomes.Impact and implicationsICIs can induce hepatitis. In this retrospective series, we report 117 cases of ICI-induced hepatitis, mostly grades 3 and 4. We find a similar distribution of the different patterns of hepatitis. ICI could be resumed without systematic recurrence of hepatitis.
| S-EPMC10149360 | biostudies-literature
Project description:Immune checkpoint inhibitors (ICI) targeting CTLA-4 and PD-1 have shown remarkable antitumor efficacy but can also cause immune-related adverse events, including checkpoint inhibitor-induced liver injury (ChILI). This multi-omic study aimed to investigate changes in blood samples from treated cancer patients who developed ChILI. PBMCs were analyzed by transcriptomic and T cell receptor sequencing (bulk and single cell), and extracellular vesicle (EV) enrichment from plasma was analyzed by mass spectroscopy proteomics. Data were analyzed by comparing the ChILI patient group to the control group who did not develop ChILI and by comparing the onset of ChILI to pre-ICI treatment baseline. We identified significant changes in T cell clonality, gene expression, and protein levels in peripheral blood mononuclear cells (PBMCs) or plasma at the time of liver injury. Onset of ChILI was accompanied by an increase in T-cell clonality. Pathway analysis highlighted the involvement of innate and cellular immune responses, mitosis, pyroptosis, and oxidative stress. Single-cell RNA sequencing revealed that these changes were primarily found in select T cell subtypes (including CD8+ effector memory cells), while CD16+ monocytes exhibited enrichment in metabolic pathways. Proteomic analysis of plasma extracellular vesicles showed enrichment in liver-associated proteins among differentially expressed proteins. Interestingly, an increase in PBMC PD-L1 gene expression and plasma PD-L1 protein was also found to be associated with onset of ChILI.
2025-01-22 | GSE287540 | GEO
Project description:Background & aimsCheckpoint inhibitors (CPI) account for increasing numbers of drug-induced liver injury (DILI) cases. We aimed to determine the incidence rate and risk factors associated with checkpoint inhibitor-induced liver injury (ChILI).MethodsPrescription event monitoring was performed on all melanoma and renal cancer patients who received CPI at a tertiary centre between 2011 and 2021. ChILI cases were identified using the definitions, grading, and causality assessment methods validated for DILI. We assessed risk factors associated with ChILI in CPI-naive patients using multivariable logistic regression model. Consecutive patients with suspected ChILI from two other tertiary centres were adjudicated and combined for case characterisation and outcomes of ChILI.ResultsOut of 432 patients who received CPI over 10 years, ChILI occurred in 38 (8.8%) with an overall incidence rate of 11.5 per 1,000 person-months (95% CI 8.2-15.8). Probability of ChILI was highest in combination therapy (32%) and no new events occurred beyond 135 days of treatment. Risk factor analysis showed that combination therapy, female sex, higher baseline alanine transferase level and lower baseline alkaline phosphatase level were independently associated with higher risk of ChILI. In total, 99 patients were adjudicated to have ChILI from three centres. Although Common Terminology Criteria for Adverse Events classified 20 patients (20.2%) to have 'life-threatening' grade 4 hepatitis, ChILI severity was graded as mild in 45 (45.5%) and moderate in the remaining 54 (54.5%) cases.ConclusionsThe real-world risk of ChILI is higher than previously reported. Among patients receiving dual CPI, this risk falls markedly after 4.5 months. As Common Terminology Criteria for Adverse Events overestimates its clinical severity, case-definition, evaluation and management of ChILI should be revised to harmonise care.Impact and implicationsUsing prescription event monitoring over a 10-year period, the incidence rate of checkpoint inhibitor induced liver injury (ChILI) based on established case definitions for drug-induced liver injury (DILI) is 11.5 per 1,000 person-months. Formal causality assessment identified an alternative cause in 19% of patients with suspected ChILI highlighting the importance of systematic evaluation by clinicians to minimise unnecessary immunosuppression. Intensity of monitoring in patients receiving combination therapy regime after 4.5 months of therapy can be reduced as the risk of new onset ChILI beyond this point is minimal. Current Common Terminology Criteria for Adverse Events (CTCAE) grading overestimates clinical severity of ChILI and hence contributes to avoidable hospitalisation.
| S-EPMC10505983 | biostudies-literature
Project description:BackgroundImmune checkpoint inhibitor (ICI)-induced pancreatic injury (ICIPI) is not well documented in the literature. We aimed to describe the clinical characteristics and outcomes of patients who developed ICIPI.MethodsWe reviewed the medical records of consecutive patients who had a confirmed diagnosis of ICIPI (Common Terminology Criteria for Adverse Events grade ≥ 3 lipase elevation with or without clinical symptoms) from April 2011 through April 2018.ResultsAmong the 2,279 patients received ICI and had lipase values checked thereafter, 82 (4%) developed ICIPI. Overall, 65% of patients received inhibitors of programmed death protein-1 or its ligand. Compared with asymptomatic presentation, patients who had clinical symptoms of pancreatitis (n = 32) had higher levels of lipase (P = 0.032), more frequent imaging evidence of pancreatitis (P = 0.055), and more frequent hospitalization (P < 0.001) and received intravenous fluids (P < 0.001) and steroids more frequently (P = 0.008). Twelve patients (15%) developed long-term adverse outcomes of ICIPI; three had chronic pancreatitis, four had recurrence of ICIPI, and six had subsequent diabetes. Among 35 patients who resumed ICI therapy, four (11%) had recurrence of lipase elevation. Logistic regression revealed that smoking and hyperlipidemia were associated with increased risk for long-term adverse outcomes of ICIPI, and intravenous fluids were associated with reduced risk. Patients who resumed ICI therapy survived longer than patients who discontinued ICI therapy permanently, statistically not significant (P = 0.0559). Patients who developed long-term adverse outcomes of ICIPI survived significantly longer than those who did not (P = 0.0295). The highest proportion of patients (6/21, 29%) developed long-term adverse outcomes of ICIPI was among those without typical symptoms of pancreatitis, continued ICI therapy after ICIPI, and did not receive intravenous fluids.ConclusionICIPI can present as typical acute pancreatitis, with risk of the development of a pseudocyst, diabetes, and chronic pancreatitis. ICI resumption after ICIPI may lead to recurrence of lipase elevation without increased risk of long-term adverse outcomes, and can increase survival duration. Intravenous fluids may prevent long-term adverse outcomes, but steroids do not appear to affect outcomes of ICIPI. Asymptomatic ICIPI presentation may lead to undertreatment of ICIPI owing to underestimation of its degree, and therefore, intravenous fluid administration could potentially could potentially be benificial to prevent long-term adverse outcomes even in asymptomatic patients.
| S-EPMC6364483 | biostudies-literature
Project description:BackgroundImmune-mediated liver injury caused by checkpoint inhibitors (ILICI) is a challenging clinical management issue. Although immunosuppressants are widely used to manage ILICI, no large-scale studies have proved definitive evidence for the most effective form of patient management.AimAnalysis of the effectiveness of immunosuppression for immune-related liver injury.MethodsWe performed a systematic review and meta-analysis of the clinical outcomes of immunosuppressive treatment of ILICI patients. A literature search of PubMed, Ovid, and Cochrane Library was completed for dates from 2000 to January 1, 2022. The primary outcome was the response rate to immunosuppressive therapy for ILICI, with subgroup analysis based on the type of cancer, immune checkpoint inhibitor regimen, and severity of liver injury. The secondary outcome was the median time to recovery from ILICI with immunosuppressive therapy.ResultsA total of 30 studies that included 1120 patients were collected. The pooled ILICI response rate was 79% (95% CI 0.73-0.84) for treatment with corticosteroids and 93% (95% CI 0.79-1.0) for treatment with mycophenolate mofetil. For ILICI treated with corticosteroids, the median recovery time was 47.59 (95% CI 39.79-55.40) days compared to 37.74 (95% CI 31.12-44.35) days for all forms of immunosuppression.ConclusionFindings support the effectiveness of corticosteroids and mycophenolate mofetil for the treatment of ILICI. The identified median time to recovery is a beneficial guide for patients and physicians, allowing for realistic expectations and appropriate treatment management. Future prospective randomized controlled trials are required to define a standardized management approach to immunosuppressive therapy of ILICI.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022313454.
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Project description: Not available
| S-EPMC7527692 | biostudies-literature
Project description:Background and aimsWhile immune checkpoint inhibitors (ICIs) are revolutionising cancer therapy, checkpoint inhibitor-induced liver injury is a significant immune-related side effect of this immunotherapy. This study focuses on the severity classifications and characteristics of patients with checkpoint inhibitor-induced hepatitis.MethodsA retrospective analysis of patients with severe Checkpoint Inhibitor-induced hepatitis grade 3 and 4 according to the recommended Common Terminology Criteria for Adverse Events (CTCAE) classification was conducted. Data on clinicobiological characteristics, treatment and outcomes were collected from 3 university hospitals, and causality was assessed by using the updated Roussel Uclaf Causality Assessment Method. The severity of hepatitis was assessed using the Model for End-stage Liver Disease score, the Drug-Induced Liver Injury Network, and the Drug-Induced Liver Injury International Expert Working Group classifications.ResultsWe retrospectively included 100 patients presenting various hepatitis patterns with a median time to onset of 20 days after checkpoint inhibitors. Severity grading varied significantly among the classifications used. A lower incidence of severe cases was observed when using the Drug-Induced Liver Injury classifications instead of the recommended CCTCAE classification, and this was correlated with outcomes.ConclusionsThis retrospective study challenges the efficacy of the CTCAE classification in defining the severity of Checkpoint Inhibitor-induced hepatitis and suggests that the traditional hepatology-focused scores may be more relevant. The CTCAE classification is inconsistent and gives equal weight to jaundice and elevated transaminases, which leads to steroid overtreatment and limits the rechallenge of ICIs.
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Project description:Immunotherapy with immune checkpoint inhibitors (ICIs) nowadays has indications for several solid tumors. The current targets for ICIs are CTLA-4, PD-1, and PD-L1 receptors. Despite the clinical advantages derived from ICIs, a variety of side effects are linked to overstimulation of the immune system. Among these, ICI-related colitis is one of the most common, with a disabling impact on the patient. Diarrhea, abdominal pain, abdominal distension, cramping, and hematochezia are the most common ICI enterocolitis presenting symptoms. The most frequently used grading system for assessment of the severity of ICI enterocolitis is called the Common Terminology Criteria for Adverse Events (CTCAE) grading. With regard to the histological picture, there is no specific feature; however, microscopic damage can be classified into five types: (1) acute active colitis, (2) chronic active colitis, (3) microscopic colitis-like, (4) graft-versus-host disease-like, and (5) other types. Supportive therapy (oral hydration, a bland diet without lactose or caffeine, and anti-diarrheal agents) is indicated in mild colitis. Symptomatic treatment alone or with loperamide, a low-fiber diet, and spasmolytics are recommended for low-grade diarrhea. In more severe cases, corticosteroid treatment is mandatory. In refractory cases, off-label use of biological therapies (infliximab or vedolizumab) was proposed.
| S-EPMC10216810 | biostudies-literature
Project description:The development of immune checkpoint inhibitors (ICIs) has been a major breakthrough in cancer immunotherapy. The increasing use of ICIs has led to the discovery of a broad spectrum of immune-related adverse events (irAEs). Immune-related myasthenia gravis (irMG) is a rare but life-threatening irAE. In this review, the clinical presentations of irMG are described and the risk of irMG-related mortality is examined using information from relevant studies. In 47 reported cases of irMG with clear causes of mortality, irMG appeared to be a distinct category of neuromuscular disorders and differed from classical MG in terms of its demographic patient characteristics, pathogenesis, serology profile, response to treatment, associated complications, and prognosis. Because of the high mortality of irMG, measures to increase the vigilance of medical teams are necessary to ensure the timely identification of the signs of irMG and early treatment, particularly in the early course of ICI therapy. The diagnostic plans should be comprehensive and include the evaluation of other organ systems, such as the dermatological, gastrointestinal, respiratory, neuromuscular, and cardiovascular systems, in addition to the traditional diagnostic tests for MG. Treatment plans should be individualized on the basis of the extent of organ involvement and clinical severity. Additional therapeutic studies on irMG in the future are required to minimize irAE-related mortality and increase the safety of patients with cancer in the ICI era.
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