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<p>Extranodal natural killer/T‑cell lymphoma (ENKTL) is a highly aggressive type of mature T and NK cell lymphoma that faces treatment challenges. Although immune checkpoint inhibitors (ICIs) have shown clinical activity in ENKTL, primary resistance and limited durable responses remain major obstacles. Our previous study demonstrated that the natural diterpenoid compound kayadiol exerted antitumor activity via p53/SLC7A11‑mediated ferroptosis in ENKTL cells. Cystine, through the solute carrier family 7 member 11 (SLC7A11)—a cystine/glutamate antiporter—serves as the primary regulator of cystine uptake for glutathione biosynthesis. To evaluate the expression patterns of SLC7A11 in ENKTL, we conducted immunohistochemistry (IHC) analyses on formalin‑fixed paraffin‑embedded (FFPE) specimens obtained from 42 newly diagnosed ENKTL patients. The results indicated that high expression of SLC7A11 was associated with decreased overall survival (OS) and progression‑free survival (PFS). Furthermore, the simultaneous detection of PD‑L1 expression revealed a correlation between the expressions of SLC7A11 and PD‑L1, with their mutual high expression also linked to an unfavorable prognosis. To further assess the co‑expression pattern of SLC7A11 and PD‑L1 in tumor cells, we performed fluorescent multiplex immunohistochemistry (mIHC). Notably, both SLC7A11 and PD‑L1 were confirmed to be predominantly localized to CD56<sup>+</sup> neoplastic cells. The mIHC analysis further substantiated that elevated co‑expression of SLC7A11 and PD‑L1 was associated with a poor prognosis for ENKTL patients. These findings were externally validated in the GSE90597 cohort, where high SLC7A11 expression and high co‑expression were both associated with poorer OS, whereas PD‑L1 alone did not reach significance. Conversely, CD8<sup>+</sup>PD‑1<sup>+</sup> tumor‑infiltrating T cells showed no statistically significant association with clinical outcomes. Our findings demonstrate that tumor cell‑specific co‑expression of SLC7A11/PD‑L1 is associated with a poor prognosis in ENKTL, suggesting that dual‑targeted therapy may enhance efficacy for these individuals.</p>

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The increased co-expression of SLC7A11 and PD-L1 was associated with poor prognosis in extranodal natural killer T-cell lymphoma patients

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月4日

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  • Cuiying He,
  • Yingzhen Yao,
  • Xiaolin Wu,
  • Meng Yue,
  • Lingling Zhang,
  • Xiaojie Fan,
  • Yuan Li,
  • Chen Zhao,
  • Haisheng Liu

摘要

Extranodal natural killer/T‑cell lymphoma (ENKTL) is a highly aggressive type of mature T and NK cell lymphoma that faces treatment challenges. Although immune checkpoint inhibitors (ICIs) have shown clinical activity in ENKTL, primary resistance and limited durable responses remain major obstacles. Our previous study demonstrated that the natural diterpenoid compound kayadiol exerted antitumor activity via p53/SLC7A11‑mediated ferroptosis in ENKTL cells. Cystine, through the solute carrier family 7 member 11 (SLC7A11)—a cystine/glutamate antiporter—serves as the primary regulator of cystine uptake for glutathione biosynthesis. To evaluate the expression patterns of SLC7A11 in ENKTL, we conducted immunohistochemistry (IHC) analyses on formalin‑fixed paraffin‑embedded (FFPE) specimens obtained from 42 newly diagnosed ENKTL patients. The results indicated that high expression of SLC7A11 was associated with decreased overall survival (OS) and progression‑free survival (PFS). Furthermore, the simultaneous detection of PD‑L1 expression revealed a correlation between the expressions of SLC7A11 and PD‑L1, with their mutual high expression also linked to an unfavorable prognosis. To further assess the co‑expression pattern of SLC7A11 and PD‑L1 in tumor cells, we performed fluorescent multiplex immunohistochemistry (mIHC). Notably, both SLC7A11 and PD‑L1 were confirmed to be predominantly localized to CD56+ neoplastic cells. The mIHC analysis further substantiated that elevated co‑expression of SLC7A11 and PD‑L1 was associated with a poor prognosis for ENKTL patients. These findings were externally validated in the GSE90597 cohort, where high SLC7A11 expression and high co‑expression were both associated with poorer OS, whereas PD‑L1 alone did not reach significance. Conversely, CD8+PD‑1+ tumor‑infiltrating T cells showed no statistically significant association with clinical outcomes. Our findings demonstrate that tumor cell‑specific co‑expression of SLC7A11/PD‑L1 is associated with a poor prognosis in ENKTL, suggesting that dual‑targeted therapy may enhance efficacy for these individuals.