Reduced NK Cell Cytotoxicity by Papillomatosis-Derived TGF-β Contributing to Low-Risk HPV Persistence in JORRP Patients

Xunyao Wu,Meiyu Liu,Zixin Zhang,Dan Guo,Yang Xiao

doi:10.3389/fimmu.2022.849493

Abstract

The role of natural killer (NK) cells in juvenile-onset recurrent respiratory papillomatosis (JORRP) patients remains elusive. In this study, we find increased NK cell percentage, particularly CD11b-CD27- (DN) subsets in peripheral blood of JORRP patients and associated with disease activity. RNA sequencing shows a downregulated “natural killer cell-mediated cytotoxicity” feature in JORRP tumors. We also find impaired cytotoxic capacity and lower expression of NK cell-activating receptors including NKp30 and NKp46. Higher transforming growth factor-beta 1 (TGF-β1) is found both in plasma and tumor tissues of JORRP, and anti-TGF-β1 antibody could restore NK cell cytolytic activity and upregulate NKp30 and NKG2D expression. Also, we find a significantly higher Chemokine receptor type 6 (CXCR6) on NK cells in tumors compared with that in peripheral blood. Finally, RT-PCR analysis show that both HPV6-E6-E7 and HPV11-E6-E7 overexpression leads to higher TGFB1 expression compared with control SNU-1076 cell line, and higher CXCR6 expression is detected on NK coculture with HPV11-E6-E7-overexpressing cells. In conclusion, we demonstrate that TGF-β1 by papillomatosis leads to decreased NK cell cytotoxicity through downregulating NK cell-activating receptors in JORRP patients.

Highlights

Human papillomavirus (HPV) is a double-stranded oncogenic DNA virus that mainly infects keratinocytes and mucosal epithelium and consists of more than 200 types [1]
We first analyze the percentage of natural killer (NK) cells in the Peripheral blood mononuclear cells (PBMCs) from healthy controls (HCs) and Juvenile-onset recurrent respiratory papillomatosis (JORRP) patients
We further compare the percentages of total NK, CD56dim NK, and CD56bright NK in different subgroups of JORRP patients based on disease severity or HPV genotyping

Summary

Introduction

Human papillomavirus (HPV) is a double-stranded oncogenic DNA virus that mainly infects keratinocytes and mucosal epithelium and consists of more than 200 types [1]. HPV carries two oncogenes, E6 and E7, which contribute to tumor growth and carcinogenesis [2]. HPV accounts for a number of distinct diseases including cutaneous warts, genital warts, and squamous intraepithelial lesions [3]. Juvenile-onset recurrent respiratory papillomatosis (JORRP), primarily caused by low-risk HPV6 and HPV11 infection, is considered as the most common benign laryngeal tumor in children that manifests with hoarseness and loss of voice [4]. Repeated costly surgical interventions place a lifetime disease burden on families [5, 6].

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