Abstract Background: Immune checkpoint inhibitors (ICIs) have transformed the therapeutic landscape of esophageal cancer (ESCA), yet a subset of patients experience hyperprogressive disease (HPD) following immunotherapy. Previous studies have suggested that genomic alterations located on chromosome 11q13—including amplification of CCND1, FGF3, FGF4, and FGF19—may contribute to HPD. This study aimed to investigate whether 11q13 amplification in ESCA is associated with genomic features or distinct immune microenvironment characteristics that could help explain resistance to immunotherapy and the development of HPD. Methods: Tumor samples from 341 ESCA patients were analyzed using a 733-gene next-generation sequencing (NGS) panel to characterize genomic profiles, including DDR pathway alterations, tumor mutation burden (TMB), and intratumor heterogeneity (ITH). Multiplex immunofluorescence (mIF) was also performed to evaluate key immune microenvironment components. Patients with and without 11q13 amplification were compared with respect to genomic alterations and immune cell infiltration. Results: Among the 341 ESCA patients, 49.3% (168/341) exhibited 11q13 amplification. Genomic analysis revealed no significant differences between the 11q13-amplified and non-amplified groups in DDR pathway gene alterations, TMB, or ITH, suggesting that 11q13-associated immunotherapy resistance is unlikely to be driven by intrinsic genomic instability. In contrast, immune microenvironment profiling demonstrated marked differences: patients with 11q13 amplification exhibited significantly reduced infiltration of FOXP3+ regulatory T cells (P=0.005) and CD3+CD4+FOXP3+ T cells (P=0.03) in the tumor stroma, while showing significantly increased infiltration and density of CD8+PD-1+ T cells in the tumor parenchyma (P=0.01 for density; P=0.02 for positivity). These immune patterns are consistent with previously reported features associated with HPD, suggesting that immune dysregulation rather than genomic alterations may underlie hyperprogression in 11q13-amplified ESCA. Conclusion: 11q13 amplification in ESCA does not correlate with DDR gene alterations, TMB, or ITH, but is strongly associated with distinct immune microenvironment features previously linked to HPD, including reduced stromal regulatory T cell infiltration and increased parenchymal CD8+PD-1+ T cell presence. These findings highlight the clinical importance of immune microenvironment dysregulation in 11q13-amplified ESCA and underscore the need for tailored therapeutic strategies for this molecular subgroup. Citation Format: Ling Deng. Immune microenvironment rather than genomic alterations drives hyperprogression-related features in 11q13 amplified Chinese esophageal cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3742.
Ling Deng (Fri,) studied this question.