Abstract
Background: Concurrent chemoradiotherapy (CRT) combined with PD-1/PD-L1 targeting immunotherapy (IM) has emerged as a promising treatment for locally advanced esophageal squamous cell carcinoma (ESCC). However, individual responses to this treatment vary, highlighting the need for predictive biomarkers to improve therapeutic efficacy. Interleukin-15 (IL-15) has shown potential in enhancing anti-tumor immunity, but its role in ESCC remains poorly defined. Methods: We analyzed clinical cohorts of ESCC patients who underwent radiotherapy (RT) and IM, utilizing blood and tissue samples collected pre- and during treatment. A multi-omics approach combining ELISA, flow cytometry, single-cell RNA sequencing, and spatial analysis was employed to investigate the role of IL-15 within the tumor microenvironment (TME). Results: Elevated IL-15 levels during RT combined with IM correlated with improved patient prognosis. IL-15 was predominantly expressed by macrophages, endothelial cells, dendritic cells, and CD4+ T cells. It enhanced the activation and maintenance of stemness in progenitor-exhausted CD8+ T (Tpex) cells via trans- or cis-presentation. The spatial proximity between presenting cells and Tpex cells was crucial for activating the IL-15 pathway and promoting immune responses within the TME. Additionally, preclinical mouse models demonstrated that combining RT, anti-PD-1, and IL-15/IL-15 receptor alpha treatment resulted in significant anti-tumor effects. Conclusions: Our findings suggest that IL-15 levels could serve as a biomarker for identifying ESCC patients who are likely to benefit from RT and IM. These results also provide a rationale for targeting IL-15 as a novel therapeutic strategy to enhance treatment outcomes for ESCC patients.