STAT3 and NF-\u03baB are Simultaneously Suppressed in Dendritic Cells in Lung Cancer

Rui Li,Wenyao Kang,Yugang Guo,Linnan Zhang,De Yang,Weihua Xiao,Zhigang Tian,Hui Zhao,Ming Jiang,Chenguang Wang,Fang Fang,Jiajia Ma,Yang Guo,Qiuyan Zhang,Dong Wang,Yuhui Miao

doi:10.1038/srep45395

Abstract

Tumour-induced dendritic cell (DC) dysfunction plays an important role in cancer immune escape. However, the underlying mechanisms are not yet fully understood, reflecting the lack of appropriate experimental models both in vivo and in vitro. In the present study, an in vitro study model for tumour-induced DC dysfunction was established by culturing DCs with pooled sera from multiple non-small cell lung cancer (NSCLC) patients. The results demonstrated that tumour-induced human monocyte-derived DCs exhibited systematic functional deficiencies. Transcriptomics analysis revealed that the expression of major functional cluster genes, including the MHC class II family, cytokines, chemokines, and co-stimulatory molecules, was significantly altered in tumour-induced DCs compared to that in control cells. Further examination confirmed that both NF-κB and STAT3 signalling pathways were simultaneously repressed by cancer sera, suggesting that the attenuated NF-κB and STAT3 signalling could be the leading cause of DC dysfunction in cancer. Furthermore, reversing the deactivated NF-κB and STAT3 signalling could be a strategy for cancer immunotherapy.

Highlights

As specialized antigen-presenting cells (APCs), dendritic cells are crucial for the initiation of adaptive immune responses[4,5]
Many in vitro models employ dendritic cell (DC) generated from peripheral blood monocytes (MoDCs) or murine bone marrow progenitor cells (BMDCs), with tumour cell line conditional medium or specific factors added in cell culture, which may not well represent the complexity of the tumour environment
These results indicate that the tumour environment manipulates DC functional deficiency by simultaneously attenuating canonical NF-κB and STAT3 signalling, leading to the abnormal transcription of downstream genes

Summary

Introduction

As specialized antigen-presenting cells (APCs), dendritic cells are crucial for the initiation of adaptive immune responses[4,5]. Tumour environment is associated with chronic inflammation, and several inflammation factors may boost the differentiation and function of DCs19,20 These anti- and pro-DC activities eventually reach a dynamic balance in DC dysfunction[21], and make it more complicated to identify the underlying mechanisms. By using lung cancer patients’ sera, we generated an in vitro model of tumour-induced DC dysfunction In this model, the ability to initiate proper anti-tumour immune responses in DCs was systematically disrupted. The disrupted upstream signalling in tumour cultured DCs, including the attenuated canonical NF-κB and STAT3 signalling pathways, may be the key reason Taken together, these results indicate that the tumour environment manipulates DC functional deficiency by simultaneously attenuating canonical NF-κB and STAT3 signalling, leading to the abnormal transcription of downstream genes

Methods

Results

Conclusion