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Background <p>Nasopharyngeal carcinoma (NPC) is an Epstein–Barr virus (EBV)-associated malignancy characterized by a highly immune-infiltrated yet clinically heterogeneous tumor microenvironment. Iron metabolism has been proposed as a potential determinant of tumor progression and immune regulation. CD44 and transferrin receptor 1 (TfR1) represent two distinct iron uptake pathways, but their relative contribution to EBV-driven NPC and immune modulation remains unclear.</p> Methods <p>Sixty-eight NPC biopsies from a Tunisian cohort were analyzed by immunohistochemistry for CD44, TfR1, EBV LMP1, PD-L1, CD8, FoxP3, and CD163. Associations with clinicopathological parameters and immune infiltrates were assessed using chi-square and Spearman correlation tests.</p> Results <p>High CD44 expression was observed in 48.5% of cases and was significantly associated with lymph node involvement (<i>p</i> = 0.012) and TNM stage (<i>p</i> = 0.042). CD44 expression positively correlated with LMP1 (<i>r</i> = 0.463, <i>p</i> = 0.001). In contrast, CD44 was inversely correlated with CD8⁺ T-cell infiltration (<i>r</i> = − 0.283, <i>p</i> = 0.019) and PD-L1 combined positive score (CPS) (<i>r</i> = − 0.247, <i>p</i> = 0.042). A significant positive correlation was observed between LMP1 and PD-L1 expression, both for tumor proportion score (TPS) (<i>r</i> = 0.341, <i>p</i> = 0.003) and CPS (<i>r</i> = 0.345, <i>p</i> = 0.002). In contrast, TfR1 expression was associated with advanced tumor stage (<i>p</i> = 0.022) but showed no significant relationship with immune parameters or LMP1. CD44 and TfR1 expression were inversely correlated (<i>r</i> = − 0.250, <i>p</i> = 0.040), suggesting alternative iron acquisition pathways.</p> Conclusion <p>Our findings suggest that CD44 may act as a key regulator linking iron metabolism and immune modulation in EBV-associated NPC. Although direct iron measurements were not performed, the observed associations with reduced CD8⁺ T-cell infiltration are consistent with a potential role of CD44 in shaping an immune-restricted tumor microenvironment. These results provide integrative evidence of a CD44–iron–immune axis in a Tunisian NPC cohort and highlight CD44 as a potential prognostic biomarker and therapeutic target.</p>

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CD44 expression associates with EBV LMP1, reduced CD8⁺ T cell infiltration, and lower PD-L1 combined positive score in nasopharyngeal carcinoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月29日

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  • Amani Sammoud,
  • Nehla Mokni Baizig,
  • Salma Kamoun,
  • Alia Methnani,
  • Yosr Zenzri,
  • Alia Mousli,
  • Maha Driss

摘要

Background

Nasopharyngeal carcinoma (NPC) is an Epstein–Barr virus (EBV)-associated malignancy characterized by a highly immune-infiltrated yet clinically heterogeneous tumor microenvironment. Iron metabolism has been proposed as a potential determinant of tumor progression and immune regulation. CD44 and transferrin receptor 1 (TfR1) represent two distinct iron uptake pathways, but their relative contribution to EBV-driven NPC and immune modulation remains unclear.

Methods

Sixty-eight NPC biopsies from a Tunisian cohort were analyzed by immunohistochemistry for CD44, TfR1, EBV LMP1, PD-L1, CD8, FoxP3, and CD163. Associations with clinicopathological parameters and immune infiltrates were assessed using chi-square and Spearman correlation tests.

Results

High CD44 expression was observed in 48.5% of cases and was significantly associated with lymph node involvement (p = 0.012) and TNM stage (p = 0.042). CD44 expression positively correlated with LMP1 (r = 0.463, p = 0.001). In contrast, CD44 was inversely correlated with CD8⁺ T-cell infiltration (r = − 0.283, p = 0.019) and PD-L1 combined positive score (CPS) (r = − 0.247, p = 0.042). A significant positive correlation was observed between LMP1 and PD-L1 expression, both for tumor proportion score (TPS) (r = 0.341, p = 0.003) and CPS (r = 0.345, p = 0.002). In contrast, TfR1 expression was associated with advanced tumor stage (p = 0.022) but showed no significant relationship with immune parameters or LMP1. CD44 and TfR1 expression were inversely correlated (r = − 0.250, p = 0.040), suggesting alternative iron acquisition pathways.

Conclusion

Our findings suggest that CD44 may act as a key regulator linking iron metabolism and immune modulation in EBV-associated NPC. Although direct iron measurements were not performed, the observed associations with reduced CD8⁺ T-cell infiltration are consistent with a potential role of CD44 in shaping an immune-restricted tumor microenvironment. These results provide integrative evidence of a CD44–iron–immune axis in a Tunisian NPC cohort and highlight CD44 as a potential prognostic biomarker and therapeutic target.