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ChemicalBook >> journal list >> Proceedings of the National Academy of Sciences of the United States of America >>article

QSOX1 facilitates dormant esophageal cancer stem cells to evade immune elimination via PD-L1 upregulation and CD8 T cell exclusion

Published:29 October 2024 DOI: 10.1073/pnas.2407506121 PMID: 39432781
Jia-Ru Wei,?Baifeng Zhang,?Yu Zhang,?Wo-Ming Chen,?Xiao-Ping Zhang,?Ting-Ting Zeng,?Yan Li,?Ying-Hui Zhu,?Xin-Yuan Guan,?Lei Li

Abstract

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.

Substances (4)

Materials
Procduct Name CAS Molecular Formula Supplier Price
Ebselen 60940-34-3 C13H9NOSe 289 suppliers $12.00-$3437.00
Ebselen 60940-34-3 C13H9NOSe 289 suppliers $12.00-$3437.00
Ebselen 60940-34-3 C13H9NOSe 289 suppliers $12.00-$3437.00
Ebselen 60940-34-3 C13H9NOSe 289 suppliers $12.00-$3437.00
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