High Serum IgA Identifies Poor Responders to Immune Checkpoint Inhibitors in Patients with Unresectable Esophageal Squamous Cell Carcinoma

BACKGROUND: Immune checkpoint inhibitors (ICIs) have become a standard first-line treatment for unresectable esophageal squamous cell carcinoma (ESCC). However, a substantial proportion of patients have early disease progression. Reliable pretreatment biomarkers capable of predicting ICI efficacy are urgently needed. Immunoglobulin A (IgA) has been implicated in shaping an immunosuppressive tumor microenvironment, yet its clinical relevance in ESCC remains unclear. METHODS: Serum IgA levels were measured in patients who had unresectable ESCC treated with first-line ICI-based therapy (n = 20) and compared with those in disease control subjects (non-ICI [n = 16] vs resectable ESCC [n = 26]) and healthy control subjects (n = 58). Associations between pretreatment serum IgA levels, survival times, and clinicopathologic variables were analyzed. The patients in each cohort were stratified into high- and low-IgA groups using cohort-specific median values. RESULTS: Serum IgA levels were significantly higher in all the ESCC patient groups than in the healthy control subjects. In the ICI-treated group, high pretreatment serum IgA was significantly associated with shorter progression-free survival (hazard ratio, 9.26; 95% confidence interval, 1.96-43.7; P = 0.005). No correlation between serum IgA and prognosis was observed in the non-ICI and resectable ESCC groups, indicating ICI-specific relevance. Pretreatment serum IgA did not correlate with clinicopathologic factors, including tumor markers and immune-related adverse events. CONCLUSIONS: High pretreatment serum IgA may serve as a novel, minimally invasive biomarker predicting poor response to ICI therapy in unresectable ESCC. Serum IgA assessment could support treatment decision-making and patient stratification in this era of expanding immunotherapy use.