QSOX1 facilitates dormant esophageal cancer stem cells to evade immune elimination via PD-L1 upregulation and CD8 T cell exclusion
成果类型：
Article
署名作者：
Wei, Jia-Ru; Zhang, Baifeng; Zhang, Yu; Chen, Wo-Ming; Zhang, Xiao-Ping; Zeng, Ting-Ting; Li, Yan; Zhu, Ying-Hui; Guan, Xin-Yuan; Li, Lei
署名单位：
Sun Yat Sen University; Sun Yat Sen University; Sun Yat Sen University; University of Hong Kong; Sun Yat Sen University; State Key Lab Oncology South China; Sun Yat Sen University; Sun Yat Sen University; University of Hong Kong
刊物名称：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
ISSN/ISSBN：
0027-15107
DOI：
10.1073/pnas.2407506121
发表日期：
2024-10-29
关键词：
摘要：
Dormant cancer stem cells (DCSCs) exhibit characteristics of chemotherapy resistance and immune escape, and they are a crucial source of tumor recurrence and metastasis. However, the underlying mechanisms remain unrevealed. We demonstrate that enriched Gzmk+ CD8+ T cells within the niche of esophageal DCSCs restrict the outgrowth of tumor mass. Nonetheless, DCSCs can escape immune elimination by enhancing PD- L1 signaling, thereby maintaining immune equilibrium. Quiescent fibroblast- derived quiescin sulfhydryl oxidase 1 (QSOX1) promotes the expression of PD- L1 and its own expression in DCSCs by elevating the level of reactive oxygen species. Additionally, high QSOX1 in the dormant tumor niche contributes to the exclusion of CD8+ T cells. Conversely, blocking QSOX1 with Ebselen in combination with anti- PD- 1 and chemotherapy can effectively eradicate residual DCSCs by reducing PD- L1 expression and promoting CD8+ T cell infiltration. Clinically, high expression of QSOX1 predicts a poor response to anti- PD- 1 treatment in patients with esophageal cancer. Thus, our findings reveal a mechanism whereby QSOX1 promotes PD- L1 upregulation and T cell exclusion, facilitating the immune escape of DCSCs, and QSOX1 inhibition, combined with immunotherapy and chemotherapy, represents a promising therapeutic approach for eliminating DCSCs and preventing recurrence.