IRAEs: The Spectrum of Immune-Related Adverse Events

Immune-related adverse events (IRAEs) are unintended consequences of immune checkpoint inhibitors, which enhance T-cell activity to fight cancer but can also trigger excessive immune responses against healthy tissues. These toxicities vary in severity and presentation, making early detection and management essential.

Understanding IRAEs requires examining the mechanisms driving immune overactivation, the role of inflammatory mediators, and how different organs are affected.

Mechanisms of T-Lymphocyte Overactivation

T-lymphocyte overactivation in IRAEs results from disrupting immune checkpoint pathways that maintain self-tolerance and prevent excessive immune responses. Checkpoint inhibitors, such as anti-CTLA-4 and anti-PD-1/PD-L1 monoclonal antibodies, remove inhibitory signals that restrain T-cell activity, enhancing tumor surveillance but also causing widespread immune dysregulation.

CTLA-4, expressed on regulatory T cells (Tregs) and activated conventional T cells, competes with CD28 for binding to B7 molecules on antigen-presenting cells. Normally, CTLA-4 reduces T-cell activation, preventing autoimmunity. Inhibiting CTLA-4 leaves CD28 signaling unopposed, sustaining T-cell stimulation and expansion. This effect is particularly pronounced in lymphoid tissues, where naïve T cells undergo priming and differentiation. CTLA-4 blockade also reduces Treg-mediated suppression, further amplifying immune activation.

PD-1 limits T-cell activity in peripheral tissues to prevent excessive inflammation. It interacts with PD-L1 and PD-L2, which are upregulated in response to inflammation. Inhibiting PD-1 prolongs T-cell survival and effector function, aiding tumor clearance but also increasing autoreactive T cells that target normal tissues. PD-1 blockade skews the T-cell repertoire, favoring highly proliferative, cytokine-producing subsets that contribute to tissue damage.

Checkpoint inhibition also disrupts the balance between effector and memory T-cell populations. After antigen clearance, most activated T cells undergo apoptosis, while some transition into memory cells. Inhibiting checkpoints disrupts this contraction phase, leading to long-lived, hyperactive T cells. Patients receiving PD-1 inhibitors often exhibit persistent T-cell activation, correlating with higher IRAE rates. Single-cell RNA sequencing has identified transcriptional profiles in these T cells, marked by upregulated cytotoxicity and inflammatory signaling genes.

Role of Cytokines in Inflammatory Cascades

Cytokines coordinate immune responses, and their dysregulation plays a central role in IRAEs. Removing inhibitory signals that regulate T-cell activity amplifies cytokine release, driving widespread inflammation. Both innate and adaptive immune cells produce pro-inflammatory mediators that sustain tissue damage. Elevated levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interferon-gamma (IFN-γ) are frequently implicated in severe IRAEs.

IL-6, a key player in acute and chronic inflammation, is markedly elevated in systemic IRAEs. It promotes Th17 cell differentiation, sustaining tissue inflammation. IL-6 also enhances C-reactive protein (CRP) production, a biomarker for inflammatory activity. IL-6 blockade with tocilizumab has shown efficacy in mitigating IRAEs, particularly immune-mediated arthritis and vasculitis.

TNF-α drives apoptosis, vascular permeability, and leukocyte recruitment. Primarily produced by activated macrophages and T cells, it plays a significant role in IRAEs affecting the gastrointestinal tract, skin, and joints. Persistent TNF-α signaling exacerbates tissue destruction by inducing matrix metalloproteinases (MMPs), which degrade extracellular matrix components. Infliximab has shown efficacy in steroid-refractory IRAEs, particularly colitis.

IFN-γ, central to T-cell-mediated immunity, is significantly upregulated in IRAEs, recruiting and activating macrophages and dendritic cells. It enhances antigen presentation and amplifies inflammation, disrupting tissue homeostasis in the lungs, liver, and endocrine glands. In pulmonary IRAEs, IFN-γ induces alveolar inflammation and fibrosis, causing dyspnea and impaired gas exchange. Janus kinase (JAK) inhibitors, which target IFN-γ signaling, have shown promise in treating severe immune-mediated pneumonitis.

Classification by Organ Involvement

IRAEs vary widely depending on the affected organ systems. Some toxicities are mild and self-limiting, while others cause significant morbidity. Severity and onset are influenced by the type of checkpoint inhibitor used, patient-specific immune responses, and genetic predispositions.

Dermatologic Manifestations

Cutaneous IRAEs are among the most common toxicities, occurring in up to 40% of patients. Manifestations range from mild maculopapular rashes and pruritus to severe conditions like Stevens-Johnson syndrome. T-cell-mediated keratinocyte destruction, driven by IFN-γ and TNF-α, underlies these effects. Histopathological findings show lymphocytic infiltration at the dermoepidermal junction, resembling autoimmune dermatoses.

Vitiligo-like depigmentation is common in melanoma patients, suggesting shared antigenic targets between tumor cells and melanocytes. Most dermatologic IRAEs respond to topical corticosteroids and antihistamines, though severe cases may require systemic immunosuppression. Early dermatologic evaluation and biopsy help distinguish IRAEs from other drug reactions.

Endocrine Manifestations

Endocrinopathies induced by checkpoint inhibitors often present insidiously, with symptoms mistaken for fatigue or metabolic disturbances. The thyroid, pituitary, and adrenal glands are most affected, with thyroid dysfunction occurring in up to 15% of patients. Thyroiditis, characterized by transient hyperthyroidism followed by hypothyroidism, results from T-cell infiltration and destruction of thyroid follicular cells. Elevated thyroid peroxidase antibodies suggest an autoimmune mechanism.

Hypophysitis, primarily associated with CTLA-4 inhibitors, leads to anterior pituitary inflammation and hormone deficiencies, including secondary adrenal insufficiency. MRI often reveals pituitary enlargement with contrast enhancement. Adrenal insufficiency, though less common, poses a risk of adrenal crisis, necessitating glucocorticoid replacement. Routine monitoring of thyroid-stimulating hormone (TSH), free T4, and morning cortisol levels aids early detection.

Pulmonary Manifestations

Immune-mediated pneumonitis, a potentially life-threatening IRAE, occurs in 3-5% of patients, with higher incidence in PD-1/PD-L1 inhibitor recipients. Lymphocytic infiltration of the alveolar interstitium impairs gas exchange, leading to respiratory distress. High-resolution CT scans often reveal ground-glass opacities or organizing pneumonia patterns.

Patients may present with dyspnea, dry cough, and hypoxemia, necessitating evaluation to rule out infection or embolism. Bronchoalveolar lavage and lung biopsy can confirm inflammation without infection. Corticosteroids are the primary treatment, with infliximab or mycophenolate mofetil reserved for refractory cases. Early recognition is critical to prevent respiratory failure.

Gastrointestinal Manifestations

Gastrointestinal IRAEs, particularly colitis, are among the most severe toxicities, occurring in up to 15% of patients, especially those receiving CTLA-4 inhibitors. Unchecked T-cell activation leads to mucosal ulceration, crypt apoptosis, and neutrophilic infiltration. Endoscopy often reveals diffuse erythema and ulcerations, resembling inflammatory bowel disease. Histopathology shows increased lamina propria lymphocytosis and crypt abscesses.

Patients typically present with diarrhea, abdominal pain, and, in severe cases, gastrointestinal bleeding. Fecal calprotectin and lactoferrin levels serve as biomarkers for disease activity. Corticosteroids are first-line treatment, with infliximab or vedolizumab for steroid-refractory cases. Severe colitis may lead to bowel perforation, requiring surgical intervention. Early gastroenterology consultation is recommended for persistent or severe symptoms.

Genetic and Epigenetic Factors

Interindividual variability in IRAEs suggests genetic and epigenetic factors influence susceptibility and severity. Genome-wide association studies (GWAS) have identified polymorphisms in immune-regulatory genes, particularly in the human leukocyte antigen (HLA) region. HLA-DRB104:05 has been linked to heightened autoimmunity following checkpoint blockade.

Beyond HLA associations, single nucleotide polymorphisms (SNPs) in CTLA4 and PDCD1, encoding CTLA-4 and PD-1, respectively, contribute to IRAE susceptibility. Variants affecting IL6 and TNF signaling pathways are associated with severe inflammatory responses, particularly in colitis and pneumonitis. Pre-treatment genetic screening could help stratify patients based on risk.

Epigenetic modifications also shape IRAE susceptibility. DNA methylation patterns in immune-regulatory genes influence T-cell reactivity, with FOXP3 hypomethylation linked to reduced immune suppression. Dysregulation of microRNAs such as miR-146a and miR-155 has been observed in severe IRAEs. These changes may persist after treatment cessation, contributing to prolonged toxicities.

Contemporary Research on Pathogenesis

Advances in single-cell sequencing and spatial transcriptomics have revealed distinct immune cell populations contributing to IRAEs. Peripheral blood mononuclear cell (PBMC) analysis has identified elevated exhaustion markers such as TIM-3 and LAG-3 in severe cases, indicating disrupted regulatory mechanisms.

Emerging biomarker research has identified predictive indicators of IRAE risk, including circulating cytokine levels, autoantibody profiles, and gene expression signatures. Elevated IL-17 and granulocyte-macrophage colony-stimulating factor (GM-CSF) levels correlate with early-onset IRAEs. Machine learning applied to multi-omics data is refining predictive models for personalized risk stratification.