The Core Problem Immune checkpoint inhibitors (ICIs) have transformed lung cancer treatment, but 14-25% of lung cancer patients have pre-existing autoimmune diseases (PADs) such as rheumatoid arthritis (RA), lupus (SLE), or psoriasis. These patients have historically been excluded from clinical trials, leaving oncologists with little guidance on how safely and effectively to use ICIs in this population.
Why ICIs Are Both Promising and Risky in PAD Patients ICIs work by releasing the brakes on the immune system, allowing it to attack cancer cells. However, in patients whose immune systems are already over-active due to autoimmune disease, removing these immune checkpoints can trigger dangerous flares of the underlying autoimmune condition or cause new immune-related adverse events (irAEs) affecting organs like the lungs, intestines, liver, and heart.
Scope of This Review This comprehensive review from Frontiers in Immunology synthesizes clinical evidence from 19 retrospective studies covering nearly 1,000 patients to provide practical guidance on ICI use in lung cancer patients with PADs, covering safety, efficacy, optimal timing, predictive biomarkers, and management strategies.
The Balancing Act The review emphasizes that decisions about ICI use in PAD patients require individualized risk-benefit assessment. Since lung cancer is life-threatening and ICIs may be the only effective option, the benefits often outweigh the risks of autoimmune flares, particularly when PADs are well-controlled before starting treatment.
Shared Inflammatory Mechanisms Autoimmune diseases and cancer share underlying pathological processes. Chronic inflammation in autoimmune conditions creates an environment of DNA damage, genomic instability, and impaired immune surveillance that can promote malignant transformation. Macrophages release matrix metalloproteinases, pro-inflammatory cytokines (IL-1, IL-6, IL-8), and reactive oxygen species that damage DNA and promote tumor development.
Immune Dysregulation Creates Cancer Risk In autoimmune diseases, an M1/M2 macrophage imbalance and impaired regulatory T cell (Treg) function leads to uncontrolled tissue damage. Chronic upregulation of immune checkpoints (PD-1/CTLA-4) in autoimmune conditions may paradoxically help pre-malignant cells evade immune destruction, creating a pathway to cancer.
Shared Genetic Risk Factors Genetic studies have identified shared susceptibility variants linking autoimmune diseases to lung cancer. Specific single nucleotide polymorphisms (SNPs) connect SLE to lung carcinogenesis, while ferroptosis-related genes (FANCD2, HELLS, VLDLR) are shared between RA and lung cancer, suggesting common biological vulnerabilities.
Immunosuppressive Treatment Risk Patients with autoimmune diseases often receive long-term immunosuppressive therapies (TNF-alpha inhibitors, IL-6 antagonists). Prolonged use exceeding 2 years correlates with a 1.3-2.5-fold increased malignancy risk, creating a compounding factor that further elevates cancer risk in this patient population.
Overall Safety Profile Analysis of 19 retrospective studies involving 468 patients with PAD and lung cancer showed that ICIs are generally safe when properly managed. PAD flare rates ranged from 5.9% to 33.3% across studies, and serious grade 3 or higher flares occurred in 0-10% of patients - rates that are higher than in patients without PADs but manageable with appropriate monitoring.
Immune-Related Adverse Events De novo irAEs (new immune reactions unrelated to the pre-existing autoimmune condition) occurred in 12.5% to 90% of patients across studies. Serious grade 3 or higher irAEs affected 3.3-26% of patients. ICI discontinuation due to flares or irAEs was required in 6.7-38% of patients. Despite these rates, most events were manageable and did not result in deaths.
PAD Flare Patterns by Disease Type Flares were most common in patients with rheumatological conditions (RA, psoriasis, psoriatic arthritis) compared to endocrine or neurological autoimmune diseases. RA was the most prevalent PAD (25.8% of patients) and showed higher rates of all-grade irAEs, though RA flares typically presented as manageable joint pain rather than life-threatening complications.
Interstitial Lung Disease Warning Patients with pre-existing interstitial lung disease (ILD) from conditions like scleroderma or RA faced substantially higher serious irAE rates (18.4% vs 9.4% for those with ILD history; 24.6% vs 8.9% for current ILD), representing the highest-risk subgroup requiring exceptional caution before starting ICIs.
Comparable or Better Outcomes Than Expected Contrary to concerns that autoimmune patients would not respond as well to ICIs, several studies found that PAD patients achieved comparable or even better responses than non-PAD patients. Objective response rates (ORR) ranged from 22% to 71.4% across six studies, and disease control rates ranged from 50% to 96%.
Survival Outcomes Median progression-free survival ranged from 2.9 to 16.5 months and median overall survival from 8.5 to 29.1 months across studies. One study (Higgins et al.) found that PAD patients tended to have longer median PFS (5.5 vs 3.5 months) and OS (17.2 vs 14.4 months) compared to patients without PAD, though differences were not statistically significant.
irAEs as Potential Efficacy Predictor An intriguing finding from Tison et al. was that experiencing a flare or de novo irAE was associated with prolonged progression-free survival in PAD patients receiving ICIs. This aligns with emerging evidence in non-PAD populations that irAEs may signal effective immune activation, though the relationship is not fully understood.
Combination Therapy Results Combination ICI plus chemotherapy showed comparable safety to ICI monotherapy in PAD patients, with no statistically significant differences in flare or irAE rates. When adjusted for baseline differences, ICI use (alone or in combination) significantly prolonged survival compared to non-ICI treatment (p = 0.0006), supporting the overall efficacy benefit.
Start When Autoimmune Disease is Controlled The key recommendation from this review is to initiate ICI therapy when the autoimmune disease is in an inactive or quiescent state. Patients with active PAD face a much higher risk of severe flares and irAEs. Before starting ICIs, the PAD should be stabilized with the minimum effective immunosuppression.
Minimize Pre-Treatment Immunosuppression Baseline corticosteroids above 10 mg/day prednisone equivalent were associated with significantly reduced ICI efficacy (reduced ORR from 42% to 28%, shorter PFS) and should be minimized before starting ICIs. Steroid-sparing agents like DMARDs and biologics were less detrimental to ICI efficacy and are preferable for maintaining PAD control.
Disease-Specific ICI Type Selection PD-1/PD-L1 inhibitors are associated with more PAD flares, while CTLA-4 inhibitors more commonly cause de novo irAEs. Patients with gastrointestinal autoimmune conditions face higher risk with dual PD-1 plus CTLA-4 combination therapy. Dermatological or endocrine PAD patients appear safer with monotherapy.
Cancer Urgency Overrides PAD Risk For advanced lung cancer with rapid progression, the life-threatening nature of the cancer justifies ICI use even in patients with active, mild-to-moderate PAD. In early or slow-progressing disease, delaying ICIs to first optimize PAD control is a safer approach. This framework requires individualized multidisciplinary decision-making.
Autoantibodies as Risk Predictors Baseline autoantibodies including anti-nuclear antibody (ANA), rheumatoid factor, anti-thyroglobulin, and anti-thyroid peroxidase antibodies have shown correlation with irAE development. Dynamic changes in autoantibody levels after ICI initiation may be even more informative than baseline levels alone, potentially enabling early detection of developing irAEs.
Cytokine Signatures Pre-treatment cytokine profiles show promise for irAE prediction. Higher baseline IL-17 or IL-6 and lower levels of TNF-alpha, IL-8, and CXCL9 correlate with increased irAE risk. Post-treatment elevations in IFN-gamma, IL-6, and CXCL10 are associated with irAE development. Elevated IL-6 specifically correlates with severe colitis.
Blood Count Indicators Routine complete blood count parameters offer practical, low-cost biomarkers. High lymphocyte count, low neutrophil count, low monocyte count, and low neutrophil-to-lymphocyte ratio (NLR) before treatment are associated with irAE risk. High baseline absolute eosinophil count specifically predicts ICI-associated pneumonitis.
Genomic Predictors Genetic variants including the SNP rs2910164 (reducing miR-146a expression) are associated with increased severe irAE risk and reduced progression-free survival. CD8+ T cell clonal expansion in peripheral blood correlates with severe irAEs in patients receiving CTLA-4 inhibitors, suggesting that monitoring T cell dynamics could help identify high-risk patients.
Grade-Based Management Protocol irAEs are graded 1-5 by severity. Grade 1 events may be monitored without stopping ICIs; grade 2 requires temporary ICI pause and moderate corticosteroids; grade 3 requires ICI discontinuation and high-dose steroids tapered over 4-6 weeks; grade 4 requires permanent discontinuation. Most irAEs resolve with this approach, and few patients ultimately must stop treatment permanently.
Resuming ICIs After Adverse Events When irAEs resolve, resuming ICI therapy is feasible for many patients. Studies show that 61% of patients who resume have no recurrent serious irAE. Gastrointestinal, liver, and lung irAEs are more likely to recur than endocrine events. Patients who had not yet responded to ICIs before the irAE benefit most from resumption, while those who had already responded may safely avoid resumption.
Next-Generation ICIs for Safer Therapy Emerging protein-engineered ICIs are designed to be active only within the tumor microenvironment, reducing systemic immune activation. Approaches include modified Fc regions reducing off-target macrophage activation, tumor-specific bispecific antibodies, and masked ICIs activated only by tumor-associated proteases (like CX-072), potentially offering equal efficacy with fewer autoimmune complications.
Dual-Purpose Treatments JAK inhibitors (like itacitinib) can control autoimmune diseases while potentially enhancing ICI efficacy. A phase II trial of pembrolizumab plus itacitinib in PD-L1-high NSCLC patients showed a 12-week ORR of 62% and median PFS of 23.8 months, with itacitinib rescuing patients who failed initial pembrolizumab alone, suggesting JAK inhibitors may serve as both AD management and ICI combination partners.