STAT3 and NF-κB are Simultaneously Suppressed in Dendritic Cells in Lung Cancer
OPEN STAT3 and NF-κB are Simultaneously Suppressed in Dendritic Cells in Lung Cancer
Rui Li 1 2
Fang Fang 1 2
Ming Jiang 1 2
Chenguang Wang 1 2
Jiajia Ma 1 2
Wenyao Kang 1 2
Qiuyan Zhang 1 2
Yuhui Miao 1 2
Dong Wang 1 2
Yugang Guo 1 2
Linnan Zhang 1 2
Yang Guo 1 2
Hui Zhao 0
De Yang 3
Zhigang Tian 1 2
Weihua Xiao 1 2
0 Department of Respiration, Second Affiliated Hospital of Anhui Medical University , Hefei , China
1 Hefei National Laboratory for Physical Sciences at Microscale, Engineering Technology Research Center of Biotechnology Drugs, Anhui Province, University of Science andTechnology of China , Hefei , China
2 The CAS Key Laboratory of Innate Immunity and Chronic Disease, Innovation Center for Cell Signaling Network, School of Life Sciences, University of Science and Technology of China , Hefei , China
3 Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick National Laboratory for Cancer Research (FNLCR) , Frederick, Maryland , USA
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 tumourinduced 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 monocytederived 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.
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Lung cancer is one of the most common malignant tumours worldwide. More than 80% of lung cancer cases are
non-small cell lung cancer (NSCLC). A high risk of metastasis in NSCLC indicates systemic anti-tumour immune
deficiency1. An inhibitor of the immune checkpoint marker PD-1 showed a remarkably reduced risk of death
compared to standard chemotherapy in NSCLC, demonstrating the importance of systematically disrupting the
suppressive immune response2. The study of tumour infiltrating immune cells revealed that dendritic cells (DCs)
infiltrating NSCLC were blocked at the immature stage, suggesting their ability to compromise tumour-specific
immune responses3.
As specialized antigen-presenting cells (APCs), dendritic cells are crucial for the initiation of adaptive immune
responses4,5. However, their antigen recognition, processing, and presenting functions are typically disrupted or
blocked during cancer development6,7. Tumour-induced DC tolerance has been suggested as pivotal in immune
evasion and cancer development8–10. Numerous studies have focused on tumour-induced DC dysfunction and
the reversal of DC tolerance as potential biological adjuvants in cancer vaccines11–13. However, tumour-induced
DCs exhibit thoroughly altered differentiation and function, and the reduction of DCs or their precursors makes
it difficult to trace the abnormal alterations and molecular mechanisms involved6,7.
To date, several cytokines and growth factors involved in the abnormal differentiation and function of
tumour-induced DCs, such as TGF-β, VEGF, and IL-10, have been identified14. TGF-β together with some
chemokines can lead to the insufficient activation and improper polarization of DCs15. In vivo administration
of VEGF in tumour-free mice can lead to impaired DC development16, and DCs from IL-10 transgenic mice
suppress antigen presentation and IL-12 production17. However, reflecting the complexity of the tumour
environment, only a number of tumour-derived factors interfere with DC function18. However, in many cases, the
tumour environment is also associated with chronic inflammation, and several inflammation factors may also
boost the differentiation and function of DCs19,20. These anti- and pro-DC activities eventually reach a dynamic
balance in DC dysfunction21, and make it more complicated to identify the underlying mechanisms.
Furthermore, current experimental models of tumour-induced DC dysfunction remain imperfect. The most
commonly used in vivo model involves tumour-infiltrating DCs (TIDCs) obtained from clinical samples or
tumour-bearing mice3,9,11. Because of the low abundance of DCs in circulation and at the tumour site, along with
individual variation, it is challenging to perform detailed analyses of the abnormal differentiation and function of
TIDCs. Many in vitro models employ DCs ge (...truncated)