QSOX1 facilitates dormant esophageal cancer stem cells to evade immune elimination via PD-L1 upregulation and CD8 T cell exclusion
Menée à l'aide de lignées cellulaires, de modèles murins et d'échantillons tumoraux prélevés sur des patients atteints d'un carcinome épidermoïde de l'oesophage, cette étude met en évidence un mécanisme par lequel la quiescine sulfhydryl oxydase 1 (QSOX1) facilite l'échappement immunitaire des cellules souches cancéreuses dormantes en favorisant l'expression de PD-L1 et l'exclusion des lymphocytes T CD8+
Résumé en anglais
Dormant tumors, akin to the Sword of Damocles, can be reactivated after an unpredictable latency period, leading to lethal recurrence. Due to the absence of effective means to eradicate dormant tumors, tumor dormancy represents one of the most formidable challenges in clinical treatment. In this study, we have revealed that quiescent fibroblast-derived quiescin sulfhydryl oxidase 1 (QSOX1) shapes an oxidative niche, facilitating dormant cancer stem cells (DCSCs) to evade immune elimination by up-regulating PD-L1 signaling and promoting the exclusion of CD8 T cells. Conversely, inhibiting QSOX1 in combination with anti-PD-1 therapy and chemotherapy can eradicate DCSCs by enhancing CD8 T cell infiltration in mice, which may represent a promising therapeutic approach to prevent relapse in patients with residual disease. 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.
