Molecular fingerprints of cardiovascular toxicities of immune checkpoint inhibitors

Basic Research in Cardiology, Год журнала: 2024, Номер unknown

Опубликована: Июль 17, 2024

Abstract Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy by unleashing the power of immune system against malignant cells. However, their use is associated with a spectrum adverse effects, including cardiovascular complications, which can pose significant clinical challenges. Several mechanisms contribute to toxicity ICIs. First, dysregulation checkpoints, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein-1 (PD-1) its ligand (PD-L1), molecular mimicry cardiac autoantigens, leads immune-related events, myocarditis vasculitis. These events result from aberrant activation T cells self-antigens within myocardium or vascular endothelium. Second, disruption homeostasis ICIs lead autoimmune-mediated inflammation tissues, manifesting dysfunction heart failure, arrhythmias, pericarditis. Furthermore, upregulation inflammatory cytokines, particularly tumor necrosis factor-alpha, interferon-γ, interleukin-1β, interleukin-6, interleukin-17 contributes endothelial dysfunction, plaque destabilization, thrombosis, exacerbating risk on long term. Understanding intricate side effects induced crucial for optimizing patient care ensure safe effective integration immunotherapy into broader range treatment protocols. The implications these underscore importance vigilant monitoring early detection in patients receiving Future key pathological mediators biomarkers may aid prompt diagnosis cardiotoxicity will allow timely interventions.

Язык: Английский

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Germline HAVCR2/TIM-3 Checkpoint Inhibitor Receptor Deficiency in Recurrent Autoinflammatory Myocarditis

Journal of Clinical Immunology, Год журнала: 2024, Номер 44(3)

Опубликована: Март 15, 2024

Myocarditis can be caused by viral infection, drug reaction or general inflammatory condition. To provide understanding on myocarditis, we describe clinical, genetic, and immunological properties of a young male patient who suffered from recurrent myocarditis episodes since the age four years. Electrocardiography, troponin I/T, echocardiography, myocardial magnetic resonance imaging histological findings were consistent with episodes. Homozygous c.245 A > G p.Tyr82Cys pathogenic variant in Hepatitis Virus Cellular Receptor 2 (HAVCR2) gene encoding T cell immunoglobulin mucin domain-containing protein 3 (TIM-3) receptor was found. Peripheral blood mononuclear cells collected when asymptomatic; CD4

Язык: Английский

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Diagnostic Value of Rock2 Protein in Immune Checkpoint Inhibitors-Associated Myocarditis

Опубликована: Янв. 1, 2025

Download This Paper Open PDF in Browser Add to My Library Share: Permalink Using these links will ensure access this page indefinitely Copy URL DOI

Язык: Английский

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Diagnostic value of ROCK2 protein in immune checkpoint inhibitors-associated myocarditis

International Journal of Cardiology, Год журнала: 2025, Номер 427, С. 133104 - 133104

Опубликована: Март 2, 2025

Язык: Английский

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ICI-induced cardiovascular toxicity: mechanisms and immune reprogramming therapeutic strategies

Frontiers in Immunology, Год журнала: 2025, Номер 16

Опубликована: Апрель 28, 2025

The advent of immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment, offering life-saving benefits to tumor patients. However, the utilize ICI agents is often accompanied by immune-related adverse events (irAEs), among which cardiovascular toxicities have attracted more and attention. induced predominantly present as acute myocarditis chronic atherosclerosis, both are driven excessive activation. Reprogramming T cells macrophages been demonstrated a pivotal factor in pathogenesis these complications. Therapeutic strategies targeting glycolysis, fatty acid oxidation, reactive oxygen species (ROS) production some other key signaling shown promise mitigating hyperactivation inflammation. In this review, we explored intricate mechanisms underlying ICI-induced highlighted protective potential reprogramming. We emphasize roles cell macrophage reprogramming heart vasculature, showcasing their contributions short-term long-term regulation health. Ultimately, deeper understanding processes will not only enhance safety ICIs but also pave way for innovative manage cancers therapy.

Язык: Английский

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Intercellular pathways of cancer treatment-related cardiotoxicity and their therapeutic implications: the paradigm of radiotherapy

Pharmacology & Therapeutics, Год журнала: 2024, Номер 260, С. 108670 - 108670

Опубликована: Май 31, 2024

Язык: Английский

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Immune-related adverse events of anti-PD-1 immune checkpoint inhibitors: a single center experience

Frontiers in Oncology, Год журнала: 2023, Номер 13

Опубликована: Окт. 17, 2023

Objectives Immune checkpoint inhibitors (ICIs) stimulate antitumor immune responses and, in parallel, they might trigger autoimmune and other immunopathological mechanisms eventually leading to immune-related adverse events (irAE). In our study, we assessed patients with malignancies who underwent anti-PD-1 treatment at the University of Debrecen, Clinical Center. Patients methods Between June 2017 May 2021, 207 started ICI university. A total 157 received nivolumab 50 were treated pembrolizumab. We looked for factors associated development irAEs. addition correlation studies, performed binary logistic regression analysis determine, which also Forward Likelihood Ratio (LR) determine independent prognostic factors. Results At time data analysis, mean duration was 2.03 ± 0.69 years. ROC determined that 9 or more cycles a significantly higher risk 125 ≥9 cycles. Three times than Of patients, 66 (32%) developed Among irAEs, 36 (55%) one, 23 (35%) two, while 7 (10%) three irAEs same patient. The most common thyroid (33 cases), dermatological (25 pneumonia (14 cases) gastrointestinal complications (13 cases). (21.8 18.7 versus 15.8 17.4; p=0.002) younger start (60.7 10.8 63.4 10.1 years; p=0.042) compared without Pembrolizumab-treated but less severe those receiving nivolumab. Conclusion is very effective, however, may develop. These be related number type malignancy.

Язык: Английский

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Therapeutic agents for steroid-refractory immune checkpoint inhibitor-related myocarditis: a narrative review

Cardiovascular Diagnosis and Therapy, Год журнала: 2024, Номер 14(4), С. 679 - 697

Опубликована: Авг. 1, 2024

Immune checkpoint inhibitors (ICIs) have become one of the cornerstones current oncology treatment, and immune inhibitor-related myocarditis (IRM) is most fatal all adverse events (irAEs). Methylprednisolone pulse therapy (500-1,000 mg/day) initial treatment for IRM recommended by almost relevant guidelines. However, subsequent regimens remain unclear patients who do not respond to methylprednisolone (who are defined as steroid-refractory patients). We propose a potential approach IRM.

Язык: Английский

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The evolving landscape of immune‐related adverse events that follow immune checkpoint immunotherapy in cancer patients

Immunological Reviews, Год журнала: 2023, Номер 318(1), С. 4 - 10

Опубликована: Авг. 26, 2023

Immune checkpoint inhibitors (ICIs), including antibodies targeting anti-cytotoxic T lymphocyte antigen 4 (CTLA-4), anti-programmed cell death 1 (PD-1), ligand (PD-L1) have revolutionized cancer treatment.1, 2 Both PD-1 and CTLA-4 are upregulated upon T-cell activation function to inhibit peripheral responses. These receptors maintain immune homeostasis, limiting tissue damage during infection helping prevent autoimmune disease. suppresses by cell-extrinsic competition with CD28 for binding the same ligands cell-intrinsic signaling mechanisms.3 The PD-1:PD-:L1/L2 pathway also responses inhibiting TCR/CD28 signaling, target lysis cytokine production.4 is expressed across a diverse set of hematopoietic non-hematopoietic cells, suggesting it may more impact in tissues, whereas its primarily secondary lymphoid organs.3 Collectively, ICI immunotherapy leverages this latter biology regulate tolerance, allowing system overcome cancer's evasion immunity reestablish ability attack tumor tissues.1, was first be approved therapy (i.e., Ipilimumab) 20115-8 treat advanced melanoma. Since then, eight agents PD-1/PD-L1 or pathways been Food Drug Administration (FDA) over 20 types 80 indications.9 Importantly, utilization ICIs adjuvant setting on rise, resulting further growth number patients receiving therapy. Cancer treated now anticipated live longer; but prolonged exposure treatment puts them at greater risk long-term complications associated line therapy.10-14 Unfortunately, success limited emergence treatment-induced inflammatory toxicities, termed immune-related adverse events (irAEs). irAEs can affect any organ body range severity, significant morbidity considerable cost healthcare system. develop after often require immunosuppressive cessation treatment, thereby potential lifesaving benefits from therapy.1, 2, 15, 16 Depending regimen drug types, combination, doses), 66%–96% irAEs, 7%–59% experience severe irAEs.17, 18 Fulminant fatal irAEs—the most common being myocarditis/myositis, pneumonitis, neurologic (e.g., Guillain–Barre syndrome myasthenia gravis)—are experienced approximately 0.4% anti-PD-1/PD-L1 monotherapy, 1.2% combination PD-1/CTLA-4 therapy.19, Toxicities manifest point they tend occur frequently within initial 3 months following initiation ICI.15, Immuno-oncology remains rapidly evolving field, many co-inhibitory beyond likely become valuable therapeutic targets near future. For example, relatlimab, compound that blocks (LAG-3) has recently use anti-PD1 therapy.21 This predominantly found exhausted cells could potentially address cell-related anergy microenvironment. As first- second-line years come, together increased as well increase anti-tumor response efficacy resistance,22, 23 expected incidence will continue rise severely limit life-saving ICIs. Intriguingly, occurring closely resemble idiopathic diseases, rheumatoid arthritis (RA), hepatitis, bowel disease.1 Further, polymorphisms various disease conditions—such Type diabetes, thyroiditis, Graves' disease, celiac systemic lupus erythematosus, arthritis15, 16, 24, 25—with which observed treatment-related share clinical features. interventions steroids, biologics agents, sometimes surgery. Insights into pathogenesis exact trigger timing known, thus implications not only care our understanding diseases. Studying cellular molecular patterns irAE provide rare window moment when patient's own starts mounting an against normal tissue. Such study enable generating novel insights mechanisms regulation throughout how tolerance.26 such, deciphering critical earliest steps driving sustaining spontaneous challenging discern such diseases fully established. While we hypothesize onset manipulation breaking tissue-specific tolerance,1, downstream involved excessive remain poorly understood. part due fact preclinical animal models yet recapitulate full spectrum presentations.15, Examples proposed far included shared antigens between affected tissue, preexisting subclinical inflammation, autoantibodies, antibody-dependent cytotoxicity, environmental insults.15, 26, 27 Given heterogeneity breadth presentations, affecting different systems pathological drivers. Among sharing similar histological characteristics specific possible multiple mechanistic endotypes result comparable manifestations. Our restricted development targeted solutions. Hitherto, management guidelines developed almost entirely based small retrospective studies expert opinion. Because toxicity severity differ, medical community conceive prospective trials each individually, opposed studying together. Over last few years, progress made biological drivers ICI-related developing effective mitigation strategies. Further research underpinning define better predictors prevention their occurrence, new, targeted, improved solutions mitigate these toxicities while preserving response. issue comprises compilation 13 review pieces top scientists experts field who discuss current systems. Reviews include several in-depth overviews presentations. They relationship response, discussions available mechanisms. cover predictive biomarkers genetic factors identified to-date, strategies used, using candidates intended improve patient outcomes. reviews summarize state-of-the complex subject, challenges therapies posed along opened questions should focus future investigations. six delves deeply organ-specific irAEs. It crucial understand immunopathology organ-systems allow personalized suppression spare negative effects immunity. Although system, barrier gastrointestinal tract, skin, liver, lungs,15, 26 three reviews. organs so commonly suggests antigenic commensal microbiome, though demonstrated. One reported vitiligo, condition characterized immune-mediated destruction melanocytes melanoma undergoing going immunotherapies.15, Vitiligo driven melanocyte antigens, produced leads melanocytes, characteristic depigmentation individuals.28 early observations, originally hypothesized other might healthy malignant similarly vitiligo. Nonetheless, majority particular type cast doubt hypothesis. Alternative hypotheses emerged discussed posit role tissue-resident memory (TRM cells), long-lived effectors reside tissues make up TRM express molecules control activation. play important roles surveillance recall pathogens.29-31 Recent investigated whether triggers promoting expansion local resident cells. work covering track, lung. Michael Dougan provides comprehensive (GI) caused ICIs.32 GI mild nature, high occurrence rate makes leading cause In his review, he description manifestations thorough discussion known to-date gut CD8+ TRMs) ICI-colitis, ICIs.33 He discusses standard care, upcoming trials, related lack trial data guide care. highlights unanswered investigation. second Blair Allais colleagues focused dermatologic reported, visible, among seen therapy.34 cutaneous (cirAEs) mild, presentations occur.35 et al. clear what about cirAEs through lenses used them. harnessing power large datasets association establish definitions cirAEs, need therapies. describe leveraging infer immunosuppression managing opportunities help Fiamma Berner Lukas Flatz two emerging classes self-antigens skin pneumonitis non-small lung therapy.36 self-antigen-specific believed dual mediating lung, creates challenge distinguishing signature those methods identification self-antigen tumors. Finally lead successful absence problematic Gary Reynolds rheumatological disabling, evolve chronic.37 superficially features rheumatic (IMRDs),38 arthritis, psoriatic Sjogren's syndrome, polymyalgia rheumatica. parallels differences IMRDs, highlight that, knowledge, clinically immunologically distinct entities. Harish Seethapathy, Kavita Mistry, Meghan Sise elegantly kidney, present acute interstitial nephritis (ICI-AIN).39 thoroughly explore manifestation ICI-AIN distinctive presentation compared conventional drug-induced AIN. authors detailed ICI-AIN, underscore diagnostic arise findings. To conclude section issue, Jingyi Gong, Tomas Neilan, Daniel A. Zlotoff myocarditis (irMyocarditis), which, all cardiovascular extensively studied substantial mortality.40 irMyocarditis occurs 1% recipients, rising increasing regimens patients.19-21, 41-43 20%–40% cases, 10-fold higher than non-ICI lymphocytic myocarditis.41-44 Nearly half cases major cardiac events, arrhythmias, cardiogenic shock, sudden death.41-44 Furthermore, near-absolute contraindication therapy, turn harm oncologic prognosis.45 frame around primary objectives. First, summary pathogenesis, compare myocardial examine categories: mediators, participating signals soluble factors, receptor (TCR) clonality specificity. Second, explaining heightened forms inflammation why affects elegant highlighting knowledge gaps requiring investigation above next includes four delve drivers, autoimmunity, leveraged underpinnings. defining underlying presents opportunity alleviate detrimental side itself. Namrata Singh, Anne Hocking, Jane Buckner interesting intersection diseases.46 phenocopy well-defined unclear truly especially ICI-associated fulminate.47 explores responsible inducing focusing ICI-diabetes, ICI-thyroiditis, ICI-arthritis. genetics autoantibodies single-cell genomic enabled signatures Ultimately, holds importance terms basic implications. Indeed, science standpoint, elucidating connection generate fundamental autoimmunity principles tolerance human. From perspective, unraveling nominate already autoimmunity. Dhodapkar, Alyssa Duffy, Madhav Dhodapkar inhibitor B-cell drive alterations compartments.48 Their involvement humoral immunity, subsets ICI. invest resources investigating cross talk B drives pathogenic contributing Noah Earland lay out perspective49 published analyzed cohort multimodal strategy involving RNA sequencing, mass cytometry blood identify development.50 showed TCR diversity circulating levels activated CD4 effector both independent affected.50 Through contextualize results comparison blood-based biomarkers. links contribute development, autoreactive located site toxicity. Finally, considered empower translation findings irAE-related tests. Presently, pathophysiological understood because mouse underestimate experience,51 do accurately replicate aspects human biology.15, 52-54 Nevertheless, there multitude tailored model patients. manuscript section, Morgan Cina, Jessica Venegas, Arabella Young put very capture some etiology underpinnings responses.55 contexts useful, improved, advantages disadvantages Approaches silico modeling datasets, vitro organoid models, vivo non-human primate canine progressed rapidly. Particularly efforts invested establishing end discussing new fidelity Better ultimately treatments. third determine ICI, predict predisposed step towards prophylactic prove making informed decisions regarding tailoring options patient. uncovering germline susceptibility variants reviewed Alexander Gusev.56 sporadic linked would heritable.57-59 summarizes mapping outcome, perspectives group genome-wide analysis IL7 irAEs,60 were subsequently independently replicated.61 extant leverage etiology, addition improving predicting There currently no FDA whom suffering outweighed Moreover, predictable treatments, chemotherapy therapy.62 map selection, prevention, monitoring initiated. Rachel Goodman, Seungyeon Jung, Justin Balko, Douglas Johnson.63 categories, help: (i) stratify pre-treatment subjects toxicities; (ii) diagnose cases; (iii) course. decision-making, alter course frequency monitoring. We Steven M. Blum, Sherin Rouhani, Ryan Sullivan treatments modulating response.64 complex65 influenced irAE-affected organ, histology, individual characteristics. maximize minimizing host environments, essential landscape populations significantly changed since approval metastatic 2011; indications curative intent. malignancies like melanoma, largely before introduction surpass risks patients, acceptable. context neoadjuvant risk-to-benefit ratio less straightforward; disease-free survival, note proportion achieve remission without ICIs, reevaluate versus reward cancer-free. illustration (Figure 1) captures complicated balance Despite remember drugs resulted good news stories, providing hopes With population, becoming increasingly support aimed root mitigated evolved remaining answered as, determining experiencing irAEs? Can What certain systems? How related? Which influence patient, transient chronic fatal? choose sparing response? Once redeveloping safely rechallenged therapy? Answering outstanding immuno-oncology field. Lastly, broad theme emerges financial disciplines cross-institutional multidisciplinary teams spanning systems, academic researchers, federal agencies, commercial partners, advocacy groups solve integrate discoveries sustainable applications. Even once identified, still necessitate collaborative endeavors infrastructure required evaluating owe find order quality life optimally benefit virtues ICI-therapy fight cancers. I wish thank Dr. John Cambier manuscripts helpful comments. Isabela Kernin her conceptualizing figure Claudia Bentley creating figure. ACV paid consultant Bristol Myers Squibb. funded National Institute Health Director's New Innovator Award (DP2CA247831), Damon Runyon-Rachleff Innovation Award, Melanoma Research Alliance Investigator (https://doi.org/10.48050/pc.gr.143739), Massachusetts General Hospital (MGH) Transformative Scholar Medicine MGH Howard Goodman Fellowship. Data applicable article.

Язык: Английский

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Identification of key immune-related genes and potential therapeutic targets in immune checkpoint inhibitor–associated myocarditis

Postgraduate Medical Journal, Год журнала: 2024, Номер unknown

Опубликована: Авг. 25, 2024

Abstract Background Immune checkpoint inhibitors (ICIs) are widely used in cancer treatment; however, the emergence of ICI-associated myocarditis (ICI-MC) presents a severe and potentially fatal complication with poorly understood pathophysiological mechanisms. This study aimed to identify crucial immune-related genes ICI-MC uncover potential therapeutic targets using bioinformatics. Methods Using GSE180045 dataset, which includes three groups—Group A: ICI patients without immune adverse events, Group B: non-myocarditis C: myocarditis—we analyzed differentially expressed (DEGs) between samples (Group C) controls (Groups A B). These DEGs were then cross-referenced 1796 from immPort database DEGs. We conducted functional enrichment analyses (Gene Ontology, Kyoto Encyclopedia Genes Genomes, gene set analysis), constructed protein–protein interaction network, identified hub genes. Validation GSE4172 dataset led identification optimal feature overlap Predictions target MicroRNAs (miRNAs) made, competing endogenous RNA (ceRNA) network was constructed. Target drugs for predicted Connectivity Map database. Results 58 controls, 32 after intersection Functional revealed cell lysis, CD8+ T-cell receptor, natural killer cell–mediated cytotoxicity, RAGE signaling. Notably upregulated included IL7R, PRF1, GNLY, CD3G, NKG7, GZMH, GZMB, KLRB1, KLRK1, CD247. In validation 407 uncovered, resulting 3 (KLRB1, GZMH). The miRNAs, lincRNAs, circRNAs constituted comprehensive ceRNA network. Among top 10 elevated connectivity scores acetohydroxamic acid, indicating need caution treatment. Conclusion KG7, KLRB1 as pivotal ICI-MC. Biological enrichments pathways involved receptor pathway, signaling, proinflammatory responses. illuminated role critical molecules underscored importance avoiding such acid Key message What is already known on this topic Myocarditis recognized serious toxicity, seemingly infrequent yet often fulminant lethal. underlying mechanisms remain not fully understood. Although significance T cells cytotoxic lymphocyte–associated protein 4 (CTLA-4) evident, inciting antigens, reasons their recognition, causing cardiac injury well characterized. An improved understanding will provide insights into equilibrium cardiovascular systems. adds Our further validates CTLA-4 myocarditis. More importantly, we genes—NKG7, KLRB1—essential development proposed networks involving these key How might affect research, practice or policy newly discovered intricate molecular interactions offer perspective Furthermore, our findings advise regarding use like during As regulatory deepens, provides valuable that could inform future strategies

Язык: Английский

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