Accumulation of LOX-1+ PMN-MDSCs in nasopharyngeal carcinoma survivors with chronic hepatitis B might permit immune tolerance to epstein–barr virus and relate to tumor recurrence

Abstract

Chronic hepatitis B (CHB) has been reported to be associated with impaired prognosis for patients with nasopharyngeal carcinoma (NPC). However, the latent mechanism is unclear. Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) induce immune suppression in CHB and promote the development of hepatocellular carcinoma. Lectin-type oxidized LDL receptor-1 (LOX-1) was recently identified as a specific marker for PMN-MSDC. We found NPC survivors with CHB had high levels of LOX-1 + PMN-MDSCs. LOX-1 + PMN-MDSCs significantly reduced T cell proliferation and activation. Endoplasmic reticulum stress was induced in LOX-1 + PMN-MDSCs. In addition, LOX-1 + PMN-MDSCs increased their expression of NOX2, a key reactive oxygen species (ROS)-related genes, and levels of ROS illustrated by the DCFDA test. The ROS inhibitor N-acetylcysteine abrogated the suppression of LOX-1 + PMN-MDSCs on T cell activation. The EBV DNA-positivity rate was higher in NPC survivors with CHB than in NPC patients without CHB. Those presenting with positive EBV DNA displayed higher LOX-1 + PMN-MDSC levels. LOX-1 + PMN-MDSCs suppressed the CD8 + T cell response against EBV. This study revealed LOX-1 + PMN-MDSC accumulation and activation in NPC survivors with CHB. LOX-1 + PMN-MDSCs might suppress the host immune response to EBV through ER stress/ROS pathway. These results explained the association of CHB with unfavorable NPC prognosis.

Endoplasmic reticulum stress mediates the myeloid-derived immune suppression associated with cancer and infectious disease

“…LOX-1+ PMN-MDSCs from NPC survivors with CHB had higher NOX2 mRNA levels, a critical ROS-related gene, suggesting that ROS mediates the immune suppressive effect of LOX-1+ PMN-MDSCs. These results suggest that PMN-MDSCs play an immunosuppressive role in the host immune response to CHB through ER stress/ROS effects [ 85 ].…”

“…M10, a novel derivative of Myricetin, prevents ER stress-induced autophagy in inflamed colonic mucosal cells by targeting the NF-κB/IL-6/STAT3 pathway, which develops M10 as a promising regimen in the chemoprevention of colitis and colorectal cancer [66]. Insights from studies might substantiate PMN-MDSCs as a potential therapeutic target for lung carcinoma [97], hepatocellular carcinoma 6, and Chronic hepatitis B (CHB) with nasopharyngeal carcinoma (NPC) [85]. Further research were warranted to confirm ER stress-related proteins, including PERK, CHOP, IRE1α, and XBP1s, as potential therapeutic targets in cancers [102][103][104].…”

The immune escape mechanism of nasopharyngeal carcinoma

“…Due to the correlation between circulating/intratumoral MDSC frequency and tumor stage, progression, treatment resistance, and recurrence, the clinical value of MDSCs has received attention. 221,222 MDSCs are amplified in the TME, including in EBVrelated NPC. EBV-LMP1-mediated glycolysis regulates the production of GM-CSF, IL-6, and IL-1β through the NLRP3 inflammasome, P-p65, and COX-2 signaling pathways to enhance tumor-related MDSC expansion, resulting in tumor immunosuppression.…”

“…Furthermore, in the nonimmunology of tumor biology, MDSCs promote angiogenesis and tumor metastasis. Due to the correlation between circulating/intratumoral MDSC frequency and tumor stage, progression, treatment resistance, and recurrence, the clinical value of MDSCs has received attention 221,222 …”

Tumor-promoting myeloid cells in the pathogenesis of human oncoviruses: potential targets for immunotherapy

“…LMP1-mediated glycolysis enhances the production of IL-1β, IL-6, and GM-CSF, the proliferation of tumor-associated MDSCs, and the inhibition of T-cells and NK cells, which lead to tumor immunosuppression [ 29 , 30 ]. The accumulation of PMN-MDSCs in nasopharyngeal cancer survivors with persistent hepatitis B may suppress the host immune response [ 31 ] to the Epstein-Barr virus and be linked to tumor recurrence via ER stress/ROS pathway.…”