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<p>Nasopharyngeal carcinoma (NPC) is prevalent in East and Southeast Asia, with genetic factors playing a significant role in its occurrence. The HLA gene region on chromosome 6 is linked to NPC susceptibility, but the mechanisms remain unclear. Epstein-Barr virus (EBV) infection is a well-established cause, with 95% of NPC patients being EBV-positive. Three key variations in the EBV genome (162215_C, 162476_C, 163364_T) in the BALF2 gene are strongly associated with NPC risk. This study finds that the high-risk BALF2 variant (BALF2-HR) upregulates HLA class II molecules, such as HLA-DP, which interacts with LAG-3 on CD8⁺ T cells, inhibiting cytokine secretion and promoting T cell exhaustion, leading to immune evasion and reduced anti-PD-1 efficacy. BALF2-HR also enhances HLA-DP transcription by binding to KPNA2 and facilitating CIITA nuclear translocation. Conjunctive immunotherapy with anti-LAG-3 and anti-PD-1 antibodies significantly improves NPC treatment. This work introduces a new therapeutic strategy for NPC and insights into infection-associated cancers.</p>

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High-risk EBV promotes immune evasion in nasopharyngeal carcinoma by upregulating HLA-DP via the encoded BALF2-HR variant

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月27日

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  • Yi Meng,
  • Qian Wang,
  • Lei Shi,
  • Qijia Yan,
  • Qianqian He,
  • Pinglang Ruan,
  • Ziwei Chen,
  • Dan Wang,
  • Hongke Qu,
  • Pan Chen,
  • Zhaojian Gong,
  • Fuyan Wang,
  • Bo Xiang,
  • Ming Zhou,
  • Ming Tan,
  • Guiyuan Li,
  • Can Guo,
  • Zhaoyang Zeng,
  • Junshang Ge,
  • Wei Xiong

摘要

Nasopharyngeal carcinoma (NPC) is prevalent in East and Southeast Asia, with genetic factors playing a significant role in its occurrence. The HLA gene region on chromosome 6 is linked to NPC susceptibility, but the mechanisms remain unclear. Epstein-Barr virus (EBV) infection is a well-established cause, with 95% of NPC patients being EBV-positive. Three key variations in the EBV genome (162215_C, 162476_C, 163364_T) in the BALF2 gene are strongly associated with NPC risk. This study finds that the high-risk BALF2 variant (BALF2-HR) upregulates HLA class II molecules, such as HLA-DP, which interacts with LAG-3 on CD8⁺ T cells, inhibiting cytokine secretion and promoting T cell exhaustion, leading to immune evasion and reduced anti-PD-1 efficacy. BALF2-HR also enhances HLA-DP transcription by binding to KPNA2 and facilitating CIITA nuclear translocation. Conjunctive immunotherapy with anti-LAG-3 and anti-PD-1 antibodies significantly improves NPC treatment. This work introduces a new therapeutic strategy for NPC and insights into infection-associated cancers.