Sex-Specific Impact of Alloimmunization on Response to Immune Checkpoint Inhibitors in NSCLC: A Prospective Translational Study

Immune checkpoint inhibitors (ICIs) have redefined the treatment of non-small cell lung cancer (NSCLC). Yet, growing evidence suggests sex-specific differences, with women often showing reduced benefit. The mechanisms are unclear. One potential factor is alloimmunization—an immune response to non-self human leukocyte antigens (HLA) acquired during pregnancy or blood transfusion, resulting in HLA alloantibodies. Such pre-existing immunity may shape both ICI efficacy and toxicity. This study examines the prevalence of HLA alloantibodies in NSCLC and their impact on outcomes, with emphasis on sex-specific patterns. The ALICE (Alloimmunization and alloantibodies in male and female NSCLC patients treated with ICIs) trial is an ongoing, prospective, single-center study, aiming to recruit 100 NSCLC patients (stage I–IV) with current or prior ICI therapy. Standardized clinical histories (pregnancy, blood transfusion, menopause, and hormone therapy) were obtained to assess alloimmunization risk and hormonal modulators. Peripheral blood samples were analyzed for HLA typing, alloantibody detection, and circulating hormone levels. The primary endpoint is the association of alloimmunization with objective response rate (ORR). Secondary endpoints include progression-free survival (PFS), overall survival (OS), and incidence of immune-related adverse events (irAEs), stratified by sex and alloimmunization status.In this interim cohort of 90 patients (44 females, 46 males), adenocarcinoma was the predominant histology (n=68), followed by squamous cell carcinoma (n=14). Most participants were current (n=44) or former smokers (n=38), with only 8 never-smokers. Alloantibodies were found in 11 patients, in several cases likely related to pregnancy. These findings already suggest measurable alloimmunization within the cohort, and the final analysis will determine whether such antibodies translate into sex-specific differences in clinical outcome once full recruitment is achieved. Alloimmunization may represent a previously underappreciated, sex-linked immunological determinant of ICI efficacy in NSCLC. Defining the clinical relevance of HLA alloantibodies could provide sex-specific biomarkers and enable more personalized immunotherapy strategies in thoracic oncology. Publication History Article published online: 04 March 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany