Restricted Recruitment of NK Cells with Impaired Function Is Caused by HPV-Driven Immunosuppressive Microenvironment of Papillomas in Aggressive Juvenile-Onset Recurrent Respiratory Papillomatosis Patients
Restricted Recruitment of NK Cells with Impaired Function Is Caused by HPV-Driven Immunosuppressive Microenvironment of Papillomas in Aggressive Juvenile-Onset Recurrent Respiratory Papillomatosis Patients
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DOI：
10.1128/jvi.00946-22
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发表时间：
2022-09
影响因子：
5.4
通讯作者：
Wei Wang;Yue Xi;Shilan Li;Xiangjun Liu;Gui-xiang Wang;Hui Wang;Meng-Miao Pei;Jie Zhang;Jingang Gui;Xin Ni
中科院分区：
文献类型：
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作者：
Wei Wang;Yue Xi;Shilan Li;Xiangjun Liu;Gui-xiang Wang;Hui Wang;Meng-Miao Pei;Jie Zhang;Jingang Gui;Xin Ni
小儿复发性呼吸道乳头状瘤病（JO-RRP）的频繁复发和侵袭性疾病进展对HPV 6/11相关喉肿瘤的完全缓解构成了巨大挑战。考虑到HPV病毒在上皮中的局部感染限制，局部免疫应答与疾病控制更相关。摘要小儿复发性呼吸道乳头状瘤病（JO-RRP）中由HPV 6/11感染引起的喉咽上皮瘤变是一个严重的健康问题，其特点是复发频繁和疾病进展迅速。由细胞毒性效应细胞的募集和激活形成的局部细胞介导的免疫对于病毒清除至关重要。在这项研究中，我们发现，NK细胞在乳头状瘤的侵略性JO-RRP患者，在大量浸润的T细胞相反，是稀缺的数量和受损的活化和细胞毒性，因为他们在外周血。细胞浸润分析表明，侵袭性JO-RRP患者NK细胞向乳头状瘤的迁移受到限制。进一步的研究表明，在侵袭性JO-RRP患者中，乳头状瘤中趋化因子的偏表达和增生上皮细胞中ICAM-1的高表达有利于T细胞而不是NK细胞的募集。在侵袭性JO-RRP患者的乳头状瘤中，我们观察到与CD 3 + T细胞增加平行的是，T细胞和Treg促进细胞因子如IL-4、IL-10和TGFβ的急剧增加。我们的研究表明，可能是由持续HPV感染的肿瘤上皮细胞的内在变化引发的，侵袭性乳头状瘤为NK细胞浸润建立了一个进入屏障，并形成了一个免疫抑制团块，以抵御来自乳头状瘤内NK细胞的免疫攻击。重要性青少年复发性呼吸道乳头状瘤病（JO-RRP）的频繁复发和侵袭性疾病进展对HPV 6/11相关喉肿瘤的完全缓解构成了巨大挑战。考虑到HPV病毒在上皮中的局部感染限制，局部免疫应答与疾病控制更相关。在我们的研究中，NK细胞数量的限制和活化NKp 30受体表达的减少提示了侵袭性JO-RRP乳头状瘤中NK细胞防御能力受损的一种可能机制。同时，HPV持续感染对NK细胞数量和功能的负面影响代表了慢性病原体颠覆NK细胞行为的另一个例子，肯定了NK细胞在病毒遏制中的潜在重要作用。此外，趋化因子/细胞因子在乳头状瘤中的偏斜表达和增生上皮细胞中粘附分子表达的升高为理解乳头状瘤中NK细胞的浸润受阻和抗病毒功能障碍提供了重要线索。
Frequent relapse and aggressive disease progression of juvenile-onset recurrent respiratory papillomatosis (JO-RRP) pose a great challenge to the complete remission of HPV 6/11 related laryngeal neoplasia. Local immune responses in papillomas are more relevant to the disease control considering the locale infected restriction of HPV virus in epitheliums. ABSTRACT Laryngopharynx epithelium neoplasia induced by HPV6/11 infection in juvenile-onset recurrent respiratory papillomatosis (JO-RRP) causes a great health issue characteristic of frequent relapse and aggressive disease progression. Local cell-mediated immunity shaped by the recruitment and activation of cytotoxic effector cells is critical for viral clearance. In this study, we found that NK cells in the papillomas of aggressive JO-RRP patients, in contrast to massive infiltrated T cells, were scarce in number and impaired in activation and cytotoxicity as they were in peripheral blood. Data from cell infiltration analysis indicated that the migration of NK cell to papilloma was restricted in aggressive JO-RRP patients. Further study showed that the skewed chemokine expression in the papillomas and elevated ICAM-1 expression in hyperplastic epithelia cells favored the T cell but not NK cell recruitment in aggressive JO-RRP patients. In parallel to the increased CD3+ T cells, we observed a dramatical increase in Tregs and Treg-promoting cytokines such as IL-4, IL-10 and TGFβ in papillomas of aggressive JO-RRP patients. Our study suggested that likely initialized by the intrinsic change in neoplastic epithelial cells with persistent HPV infection, the aggressive papillomas built an entry barrier for NK cell infiltration and formed an immunosuppressive clump to fend off the immune attack from intra-papillomas NK cells. IMPORTANCE Frequent relapse and aggressive disease progression of juvenile-onset recurrent respiratory papillomatosis (JO-RRP) pose a great challenge to the complete remission of HPV 6/11 related laryngeal neoplasia. Local immune responses in papillomas are more relevant to the disease control considering the locale infected restriction of HPV virus in epitheliums. In our study, the restricted NK cell number and reduced expression of activating NKp30 receptor suggested one possible mechanism underlying impaired NK cell defense ability in aggressive JO-RRP papillomas. Meanwhile, the negative impact of HPV persistent infection on NK cell number and function represented yet another example of a chronic pathogen subverting NK cell behavior, affirming a potentially important role for NK cells in viral containment. Further, the skewed chemokine/cytokine expression in the papillomas and the elevated adhesion molecules expression in hyperplastic epithelia cells provided important clues for understanding blocked infiltration and antiviral dysfunction of NK cells in papilloma.