Dexamethasone and lactoferrin induced PMN-MDSCs relieved inflammatory adverse events of anti-cancer therapy without tumor promotion

Xing Li,Yan-Fang Xing,Nan Jiang,Jie Chen,Yong-Jian Chen,Yi-Dan Qiao,Xiang-Yuan Wu,Li-Yun Zhao

doi:10.1038/s42003-021-01769-z

Abstract

In this era of immune checkpoint inhibitors, inflammatory adverse events of anti-cancer therapies continue to pose a major challenge. Glucocorticoids, as the mainstay, were limited by serious side effects. Glucocorticoids induce myeloid-derived suppressor cells (MDSCs), and lactoferrin-induced polymorphonuclear MDSCs (PMN-MDSCs) were shown to relieve inflammatory conditions. Combined treatment with dexamethasone (DXM) and lactoferrin increased the generation of PMN-MDSCs in vitro (DXM/lactoferrin PMN-MDSCs) compared to DXM or lactoferrin treatment alone. DXM/lactoferrin PMN-MDSCs were distinct from tumor PMN-MDSCs in vivo with regard to gene expression profiles. DXM upregulated the myeloid cell response to lactoferrin by inducing the lactoferrin receptor Lrp1. DXM/lactoferrin PMN-MDSCs presented anti-bacterial capability, increased PGE2 production, increased survival capability, and decreased tumor tissue homing. Transfer of DXM/lactoferrin PMN-MDSCs relieved cisplatin-induced acute kidney failure, bleomycin-induced interstitial pneumonia, and allergic pneumonitis effectively without promoting tumor development. Our study shows that DXM/lactoferrin PMN-MDSCs are a promising cell therapy for inflammatory adverse events of anti-cancer therapies.

Highlights

In this era of immune checkpoint inhibitors, inflammatory adverse events of anti-cancer therapies continue to pose a major challenge
We found that lactoferrin-induced myeloid-derived suppressor cells (MDSCs) in vitro were efficient in treating inflammatory disease in tumorfree neonatal mice[15], and hypothesized that the efficacy may be further enhanced by the administration of glucocorticoid
bone marrow (BM) cells from 6–8-week-old mice were cultured for 72 h with granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-6, lactoferrin (600 μg/ ml) and DXM were added with phosphate buffer saline (PBS) as control

Summary

Introduction

In this era of immune checkpoint inhibitors, inflammatory adverse events of anti-cancer therapies continue to pose a major challenge. Transfer of DXM/lactoferrin PMN-MDSCs relieved cisplatin-induced acute kidney failure, bleomycin-induced interstitial pneumonia, and allergic pneumonitis effectively without promoting tumor development. Our study shows that DXM/lactoferrin PMN-MDSCs are a promising cell therapy for inflammatory adverse events of anti-cancer therapies. In cancer patients, MDSCs induced immune tolerance to tumor antigens and promoted the development of cancer[16,17], which impedes their use in controlling inflammatory adverse events during anti-cancer therapy. We found that dexamethasone (DXM)- and lactoferrin-induced PMN-MDSCs presented immunosuppressive function, antibacterial capability, improved survival, decreased tumor tissue homing, as well as a distinct gene profile from the tumor PMN-MDSCs. DXM- and lactoferrin-induced PMN-MDSCs relieved anti-cancer therapy-related inflammatory adverse events without promoting tumor progression. In vitro DXM- and lactoferrin-induced PMN-MDSCs may be a remedy for the prevention and treatment of inflammatory adverse events associated with anti-cancer therapy

Methods

Results

Conclusion