Overexpression of S100A9 in tumor stroma contribute to immune evasion of NK/T cell lymphoma and predict poor response rate

Zhiyuan Zhou,Xinfeng Chen,Xinhua Wang,Zhaoming Li,Mingzhi Zhang

doi:10.1038/s41598-021-90794-3

Zhiyuan Zhou, Xinfeng Chen + Show 3 more

Open Access

https://doi.org/10.1038/s41598-021-90794-3

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Abstract

NK/T cell lymphoma (NKTCL) represents an aggressive lymphoid malignancy characterized by dismal prognosis. Immune-checkpoint blockade has shown promising efficacy in NKTCL. However, the molecular mechanisms underlying immune evasion in NKTCL have never been explored. Here, proteomic analysis was used to identify the differentially expressed proteins between NKTCL patients and healthy individuals. We found that S100A9, an immunosuppressive molecule, was much higher in NKTCL patients both in serum and tumor stroma. Elevated level of S100A9 was associated with advanced stage, poor overall response and early recurrence. Moreover, percentage of myeloid-derived suppressor cells (MDSCs) in peripheral blood was positively correlated with levels of S100A9. Low concentration of S100A9 promoted proliferation of NKTCL cells, while did not affect cell apoptosis and cell cycles. Furthermore, programmed death ligand 1 (PD-L1) expression on NKTCL cells was up-regulated by S100A9 through activation of ERK1/2 signaling. Inhibition of ERK1/2 signaling significantly decreased tumor growth and PD-L1 expression induced by S100A9. In conclusion, our research firstly identified S100A9 as an immune suppressor in the tumorigenesis of NKTCL via accumulation of MDSCs and upregulation of PD-L1 expression. S100A9 may serve as a potential target to increase the efficacy of immunotherapy in NKTCL.

Highlights

NK/T cell lymphoma (NKTCL) represents an aggressive lymphoid malignancy characterized by dismal prognosis
Enzyme‐linked immunosorbent assay (ELISA) assay further confirmed that NKTCL patients presented higher levels of serum S100A9 than healthy individuals (p < 0.001) (Fig. 2A)
Immunohistochemical staining showed that normal nasal mucosa tissues did not express S100A9, while S100A9 was highly expressed by tumor stromal cells in NKTCL (Fig. 2B)

Summary

Introduction

NK/T cell lymphoma (NKTCL) represents an aggressive lymphoid malignancy characterized by dismal prognosis. Proteomic analysis was used to identify the differentially expressed proteins between NKTCL patients and healthy individuals. Programmed death ligand 1 (PD-L1) expression on NKTCL cells was up-regulated by S100A9 through activation of ERK1/2 signaling. EBV-encode LMP-1 was reported to be able to activate NF-KB signaling and increased PD-L1 expression in NKTCL cells[13]. We conducted proteomic analysis to identify the differentially expressed proteins in serum from NKTCL patients and healthy individuals. S100A9 was confirmed to be elevated in both serums and tumor stroma from NKTCL patients. Clinical analysis implied that high expression of S100A9 in tumor stroma predicted advanced stage, poor response rate and early recurrence. S100A9 protein promoted proliferation and increased PD-L1 expression in NKTCL cells via activation of ERK1/2 pathway. S100A9 may mediate inflammation-associated NKTCL and function as a novel target to improve the management of NKTCL patients

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