Clinical Significance of <scp>PD</scp> ‐ <scp>L1</scp> and <scp>HLA</scp> Expression in Esophageal Squamous Cell Carcinoma in Response to Immunotherapy

ABSTRACT Despite recent advances in multimodal therapy, esophageal squamous cell carcinoma (ESCC) remains a highly lethal malignancy. Although immune checkpoint inhibitors (ICIs) have improved clinical outcomes, predictive biomarkers are urgently needed. This study aimed to investigate immune‐related features in tumor cells and the tumor microenvironment in pathological specimens from 45 patients with ESCC treated with ICIs for postoperative recurrence after curative resection. Immunohistochemistry and quantitative image analysis of CD3, CD8, FoxP3, CD163, PD‐L1, HLA‐A/B/C, and HLA‐DR were conducted. High programmed death‐ligand 1 (PD‐L1) expression in tumor‐associated macrophages (TAMs) and tumor cells was significantly associated with a favorable response. Infiltration of T cells, regulatory T cells, and TAMs was not associated with the clinical response, but increased T‐cell infiltration was closely associated with high PD‐L1 expression in TAMs. Downregulation of HLA‐A/B/C and ectopic HLA‐DR expression was seen in responders. High PD‐L1 expression in TAMs was closely related to increased T‐cell infiltration, and single‐cell RNA‐sequence analysis suggested a significant correlation with T‐cell proliferation. Collectively, these findings indicate that not only PD‐L1, but also HLA expression is useful for predicting the effectiveness of ICI therapy in patients with ESCC.