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Background <p>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.</p> Methods <p>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).</p> Results <p>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<sup>+</sup> T cells. It enhanced the activation and maintenance of stemness in progenitor-exhausted CD8<sup>+</sup> 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.</p> Conclusions <p>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.</p> Graphical abstract <p></p>

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IL-15 signaling via cis- and trans-presentation to progenitor-exhausted CD8+ T cells enhances radio-immunotherapy efficacy in ESCC

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月1日

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  • Yi You,
  • Linrui Gao,
  • Shijia Li,
  • Hui Huang,
  • Tierun Wang,
  • Zongchang Nie,
  • Jian Zhou,
  • Xiaoxue Ma,
  • Jiarui Li,
  • Hongyu Bie,
  • Tian Zhang,
  • Xi Chen,
  • Qingsong Pang,
  • Ping Wang,
  • Cihui Yan,
  • Wencheng Zhang

摘要

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.

Graphical abstract