Humans with inherited T cell CD28 deficiency are susceptible to skin papillomaviruses but are otherwise healthy.

We study a patient with the human papilloma virus (HPV)-2-driven "tree-man" phenotype and two relatives with unusually severe HPV4-driven warts. The giant horns form an HPV-2-driven multifocal benign epithelial tumor overexpressing viral oncogenes in the epidermis basal layer. The patients are unexpectedly homozygous for a private CD28 variant. They have no detectable CD28 on their T cells, with the exception of a small contingent of revertant memory CD4+ T cells. T cell development is barely affected, and T cells respond to CD3 and CD2, but not CD28, costimulation. Although the patients do not display HPV-2- and HPV-4-reactive CD4+ T cells in vitro, they make antibodies specific for both viruses in vivo. CD28-deficient mice are susceptible to cutaneous infections with the mouse papillomavirus MmuPV1. The control of HPV-2 and HPV-4 in keratinocytes is dependent on the T cell CD28 co-activation pathway. Surprisingly, human CD28-dependent T cell responses are largely redundant for protective immunity.

K-Ras Promotes Tumorigenicity through Suppression of Non-canonical Wnt Signaling.

K-Ras and H-Ras share identical effectors and have similar properties; however, the high degree of tumor-type specificity associated with K-Ras and H-Ras mutations suggests that they have unique roles in oncogenesis. Here, we report that oncogenic K-Ras, but not H-Ras, suppresses non-canonical Wnt/Ca(2+) signaling, an effect that contributes strongly to its tumorigenic properties. K-Ras does this by binding to calmodulin and so reducing CaMKii activity and expression of Fzd8. Restoring Fzd8 in K-Ras mutant pancreatic cells suppresses malignancy, whereas depletion of Fzd8 in H-Ras(V12)-transformed cells enhances their tumor initiating capacity. Interrupting K-Ras-calmodulin binding using genetic means or by treatment with an orally active protein kinase C (PKC)-activator, prostratin, represses tumorigenesis in K-Ras mutant pancreatic cancer cells. These findings provide an alternative way to selectively target this "undruggable" protein.

Characterization of HPV6/11-reactive T-cell subsets in papillomas of patients with juvenile-onset recurrent respiratory papillomatosis and identification of HPV11 E7-specific candidate TCR clonotypes.

Juvenile-onset recurrent respiratory papillomatosis (JORRP) is caused by persistent infection of epithelial cells by low-risk human papillomavirus (HPV) types 6 and 11. While multiple infiltrated immune cells have been reported to mediate disease progress, knowledge of HPV-reactive T-cell subsets in papillomas remains elusive. Through single-cell RNA sequencing and RNA microarray, we found that CD8+ tissue-resident memory T (CD8+ TRM) cells with strong interferon-gamma (IFN-γ) production expanded, and were negatively correlated to the disease severity in the frequency of surgery. These IFN-γ+ CD8+ memory T cells were readily activated and expanded in vitro by autologous dendritic cells loaded with HPV11 E7 peptide pool. Moreover, T cell receptor (TCR) clonal expansion was observed in JORRP papilloma tissues, indicating a biased TCR repertoire toward HPV-specific recognition. Finally, we identified and characterized HPV11 E7-specific candidate TCR clonotypes from IFN-γ+ CD8+ memory T cells, suggesting their potential application in TCR-engineered T cells (TCR-T) therapy for HPV11-related diseases. Our findings provided insights into the specific local immune response to HPV6/11 infection and highlighted the importance of IFN-γ+ CD8+ TRM cells in anti-HPV6/11 T-cell immunity.IMPORTANCEThe persistent recurrence of human papillomavirus (HPV) 6/11 infection in papillomas underscores the failure of local immune responses in patients with juvenile-onset recurrent respiratory papillomatosis (JORRP). Our previous study demonstrated that T cells constitute the predominant immune cell population in JORRP papilloma tissues. Understanding the T-cell-mediated immune responses within JORRP papilloma tissues is crucial for disease control. In the present study, we characterized CD8+ tissue-resident memory T (CD8+ TRM) cells as the primary T-cell subset responsible for local anti-HPV6/11 immunity. Moreover, we identified two HPV11 E7-specific candidate T cell receptor (TCR) clonotypes out of IFN-γ+ CD8+ memory T cells. Overall, our findings provided insights into the local immune responses to HPV6/11 infection and offered information for developing more effective immunotherapeutic strategies against JORRP.

Further pharmacological and genetic evidence for the efficacy of PlGF inhibition in cancer and eye disease.

Our findings that PlGF is a cancer target and anti-PlGF is useful for anticancer treatment have been challenged by Bais et al. Here we take advantage of carcinogen-induced and transgenic tumor models as well as ocular neovascularization to report further evidence in support of our original findings of PlGF as a promising target for anticancer therapies. We present evidence for the efficacy of additional anti-PlGF antibodies and their ability to phenocopy genetic deficiency or silencing of PlGF in cancer and ocular disease but also show that not all anti-PlGF antibodies are effective. We also provide additional evidence for the specificity of our anti-PlGF antibody and experiments to suggest that anti-PlGF treatment will not be effective for all tumors and why. Further, we show that PlGF blockage inhibits vessel abnormalization rather than density in certain tumors while enhancing VEGF-targeted inhibition in ocular disease. Our findings warrant further testing of anti-PlGF therapies.

PGE2 expression by HPV6/11-induced respiratory papillomas blocks NK cell activation in patients with recurrent respiratory papillomatosis.

Recurrent respiratory papillomatosis (RRP), a rare chronic disease caused primarily by human papillomavirus types 6 and 11, consists of repeated growth of premalignant papillomas in the airway. RRP is characterized by multiple abnormalities in innate and adaptive immunity. Natural killer (NK) cells play important roles in immune surveillance and are part of the innate immune responses that help prevent tumor growth. We identified that papillomas lack classical class I MHC and retain nonclassical class I MHC expression. Moreover, in this study, we have identified and characterized the mechanism that blocks NK cell targeting of papilloma cells. Here, we show for the first time that the PGE2 secreted by papilloma cells directly inhibits NK cells activation/degranulation principally through the PGE2 receptor EP2, and to a lesser extent through EP4 signaling. Thus, papilloma cells have a potent mechanism to block NK cell function that likely supports papilloma cell growth.

Clinical, onychoscopic, nail clipping, and histopathological findings of malignant onychopapilloma.

This report describes the clinical, onychoscopic, nail clipping, and histopathologic features of a malignant onychopapilloma. A 71-year-old male presented to our outpatient clinic for a stable, asymptomatic lesion on his left middle finger that had been present for 2 years. Prior nail clipping histopathology showed nail plate thinning with subungual abnormal onychocytes. Clinical examination revealed a 2-mm-wide streak of longitudinal xanthonychia extending to the proximal nail fold, with distal hyperkeratosis and onycholysis. Onychoscopy showed irregular longitudinal nail plate ridging with scattered punctate hemorrhagic foci. An excisional nail unit biopsy demonstrated cellular atypia of the nail bed epithelium, matrix metaplasia, longitudinal abnormal onychocytes, increased Ki-67 staining, and negative HPV immunoperoxidase staining, confirming the diagnosis of malignant onychopapilloma.

The possible role of haematophagous flies in the incidence of bovine teat papillomatosis.

The relationship between the incidence of bovine teat papillomatosis and the activity of haematophagous flies was investigated in Japan. A total of 15,737 flies consisting of 33 species were collected by dry ice-baited mosquito net (DMN) trap and a sweep net from udders of cattle. Simulium aokii (Takahasi) of Simuliidae (black flies) was the predominant species, followed by S. tobetsuense Ono and S. iwatense (Shiraki). Simulium aokii had the highest peak in October, followed by September. Numbers of blood spots from the bites per teat in nulliparous cattle were significantly correlated with numbers of S. aokii collected by DMN trap. Numbers of teats with warts and spots of blood from the bites per teat were significantly more abundant in anterior teats than posterior teats. The average incidence of teat papillomatosis in nulliparous cattle was significantly higher than that in parous cattle, and the highest incidence by month was in May, followed by April. Although bovine papillomavirus (BPV) DNA was not detected in flies examined, the presence of black flies and blood spots from their bites were associated with subsequent high incidence of growing warts. In particular, it would pay to give attention to species such as S. aokii that severely attack udders in the present locality. Further investigations for the detection of BPV DNA from flies parasitizing on teats are needed.

Human Papilloma Virus-Infected Cells.

Human papillomavirus (HPV) is associated with infection of different tissues, such as the cervix, anus, vagina, penis, vulva, oropharynx, throat, tonsils, back of the tongue, skin, the lungs, among other tissues. HPV infection may or may not be associated with the development of cancer, where HPVs not related to cancer are defined as low-risk HPVs and are associated with papillomatosis disease. In contrast, high-risk HPVs (HR-HPVs) are associated with developing cancers in areas that HR-HPV infects, such as the cervix. In general, infection of HPV target cells is regulated by specific molecules and receptors that induce various conformational changes of HPV capsid proteins, allowing activation of HPV endocytosis mechanisms and the arrival of the HPV genome to the human cell nucleus. After the transcription of the HPV genome, the HPV genome duplicates exponentially to lodge in a new HPV capsid, inducing the process of exocytosis of HPV virions and thus releasing a new HPV viral particle with a high potential of infection. This infection process allows the HPV viral life cycle to conclude and enables the growth of HPV virions. Understanding the entire infection process has been a topic that researchers have studied and developed for decades; however, there are many things to still understand about HPV infection. A thorough understanding of these HPV infection processes will allow new potential treatments for HPV-associated cancer and papillomatosis. This chapter focuses on HPV infection, the process that will enable HPV to complete its HPV life cycle, emphasizing the critical role of different molecules in allowing this infection and its completion during the HPV viral life cycle.

Dermatological manifestations in Costello syndrome: A prospective multicentric study of 31 HRAS-positive variant patients.

BACKGROUND: Data on dermatological manifestations of Costello syndrome (CS) remain heterogeneous and lack in validated description. OBJECTIVES: To describe the dermatological manifestations of CS; compare them with the literature findings; assess those discriminating CS from other RASopathies, including cardiofaciocutaneous syndrome (CFCS) and the main types of Noonan syndrome (NS); and test for dermatological phenotype-genotype correlations. METHODS: We performed a 10-year, large, prospective, multicentric, collaborative dermatological and genetic study. RESULTS: Thirty-one patients were enrolled. Hair abnormalities were ubiquitous, including wavy or curly hair and excessive eyebrows, respectively in 68% and 56%. Acral excessive skin (AES), papillomas and keratotic papules (PKP), acanthosis nigricans (AN), palmoplantar hyperkeratosis (PPHK) and 'cobblestone' papillomatous papules of the upper lip (CPPUL), were noted respectively in 84%, 61%, 65%, 55% and 32%. Excessive eyebrows, PKP, AN, CCPUL and AES best differentiated CS from CFCS and NS. Multiple melanocytic naevi (>50) may constitute a new marker of attenuated CS associated with intragenic duplication in HRAS. Oral acitretin may be highly beneficial for therapeutic management of PPHK. No significant dermatological phenotype-genotype correlation was determined between patients with and without HRAS c.34G>A (p.G12S). CONCLUSIONS AND RELEVANCE: This validated phenotypic characterization of a large number of patients with CS will allow future researchers to make a positive diagnosis, and to differentiate CS from CFCS and NS.

Ultrasound Features of Onychopapilloma at High-Frequency and Ultra-High Frequency.

OBJECTIVE: This study aimed to identify the sonographic features of pathologically confirmed onychopapilloma cases. METHODS: High-frequency up to 24 MHz and ultra-high frequency-ultrasound up to 71 MHz examinations were performed and correlated with their clinical and pathologic presentations. RESULTS: Twenty-two cases met the criteria. Clinical presentations revealed longitudinal erythronychia in 63.3% of cases. The ultrasound examinations identified a hypoechoic band in the nail bed (86.3%), nail plate abnormalities including upward displacement (68.2%) and thickening (68.1%), focal hyperechoic focal spots on the nail plate (50%) and irregularities of the ventral plate (33.3%). Color Doppler imaging showed no hypervascularity of the nail bed in all studies. These findings correlate with histological characteristics of onychopapilloma, including nail bed acanthosis, papillomatosis, and layered hyperkeratosis. Recurrence occurred in two cases after surgery, with tumors showing proximal extension in the matrix region on ultrasound not evident during clinical examination. CONCLUSION: High-frequency and ultra-high-frequency can provide anatomical information in onychopapilloma that could enhance understanding and management.

Dual Sec62/Ki67 immunocytochemistry of liquid-based cytological preparations represents a highly valid biomarker for non-invasive detection of head and neck squamous cell carcinomas.

BACKGROUND: Head and neck squamous cell carcinomas (HNSCC) are frequently diagnosed in advanced stages, which limits therapeutic options and results in persistently poor patient outcomes. The aim of this study was to use liquid-based swab cytology (LBC) in combination with dual immunocytochemical detection of migration and proliferation markers Sec62 and Ki67 in order to allow non-invasive early detection of HNSCC as well as to analyse the diagnostic validity of this method for predicting the malignancy of suspicious oral lesions. METHODS: 104 HNSCC patients and 28 control patients, including healthy patients (n = 17), papilloma (n = 1) and leukoplakia patients (n = 10), were included in this study. For all patients, an LBC swab followed by simultaneous immunocytochemical detection of Sec62 and Ki67 was performed. Immunocytochemical as well as cytopathological results were correlated with histological diagnoses and clinical findings. RESULTS: All HNSCC patients (100%) showed dual Sec62/Ki67 positivity, and all control patients except for the papilloma patient were negative for Sec62/Ki67 (96.4%), resulting in a 100% sensitivity and 96.4% specificity of Sec62/Ki67 dual stain for non-invasive detection of HNSCC. The positive predictive value was 99% and the negative predictive value was 100%. Sec62 expression levels showed a positive correlation with tumour de-differentiation (p = 0.0489). CONCLUSION: Simultaneous immunocytochemical detection of Sec62/Ki67 using LBC represents a promising non-invasive and easy-to-apply tool for the early detection of HNSCC in routine clinical practice. This novel technique can help to avoid incisional biopsies and reduce the frequency with which general anaesthesia is used in diagnostic procedures in patients with suspicious oral lesions.

The clinical characteristics of 1894 cases of upper respiratory papillomatosis: A single-center retrospective analysis.

BACKGROUND: With advancements in medicine and economy, it would be expected that there will be changes in the clinical characteristics of upper respiratory papillomatosis. The aim of this study was to examine the current clinical characteristics of upper respiratory papillomatosis, as there are no recent data in the literature. METHODS: The medical records of 1894 patients with upper respiratory papillomatosis were retrospectively reviewed. Data extracted included clinical features, laryngoscopy images, and surgical procedure data. RESULTS: The upper frequency of upper respiratory papillomatosis in the oropharynx was 69.1 %, and in the larynx was held 28.9 %. The overall postoperative relapse rate was 2.4 %. The relapse rate of laryngeal papillomatosis was 6.5 %. Approximately 2.6 % of cases were in children. All postoperative recurrences in children were laryngeal, and the recurrence rate was 30.4 %. CONCLUSION: The oropharynx has the highest frequency of upper respiratory papillomatosis. The larynx, however, has the highest rate of postoperative recurrence. Compared to adults, children are more likely to experience a postoperative recurrence.

Long-Term Outcome for Primary Papillomas of the Lacrimal Drainage System.

PURPOSE: To report long-term outcomes after surgery for primary benign papillomas of the lacrimal drainage system. METHODS: Retrospective review of patients with primary lacrimal drainage system papillomas, first seen between 1984 and 2021, but excluding lesions with sino-nasal origin or malignant histology. Patients were categorized by tumor histology (squamous, transitional, and mixed cell) and growth pattern (exophytic, endophytic, or mixed). RESULTS: Thirty patients (18 female; 60%) presented at a mean age of 46.1 years (12-79 years). Over an average follow-up of 10.4 years, 30% of patients experienced recurrence, with rates differing slightly by growth pattern: 25% for exophytic tumors and 40% for endophytic and mixed-pattern tumors ( p = 0.431). The overall 5-year recurrence-free survival was 67% (± 9% standard error), this being slightly higher for exophytic lesions (75% ± 10%) as compared to 48% (± 19%) for tumors with an endophytic component ( p = 0.370). No cases of malignant transformation were observed, and the tumor type at recurrence matched the initial diagnosis. CONCLUSION: Primary benign papillomas of the lacrimal drainage system have a long-term recurrence rate of about one-third, with a higher frequency in those exhibiting an endophytic growth pattern. The study highlights the importance of prolonged surveillance for recurrence, especially for endophytic and mixed growth pattern tumors, and for the potential to undergo malignant transformation. The results support the effectiveness of endoscopic surgical excision or laser thermos-ablation in managing recurrent lacrimal drainage system papillomas after dacryocystorhinostomy.

The Diagnostic Value of microRNA Expression Analysis in Detecting Intraductal Papillomas in Patients with Pathological Nipple Discharge.

Patients with pathological nipple discharge (PND) often undergo local surgical procedures because standard radiologic imaging fails to identify the underlying cause. MicroRNA (MiRNA) expression analysis of nipple fluid holds potential for distinguishing between breast diseases. This study aimed to compare miRNA expression levels between nipple fluids from patients with PND to identify possible relevant miRNAs that could differentiate between intraductal papillomas and no abnormalities in the breast tissue. Nipple fluid samples from patients with PND without radiological and pathological suspicion for malignancy who underwent a ductoscopy procedure were analyzed. We used univariate and multivariate regression analyses to identify nipple fluid miRNAs differing between pathologically confirmed papillomas and breast tissue without abnormalities. A total of 27 nipple fluid samples from patients with PND were included for miRNA expression analysis. Out of the 22 miRNAs examined, only miR-145-5p was significantly differentially expressed (upregulated) in nipple fluid from patients with an intraductal papilloma compared to patients showing no breast abnormalities (OR 4.76, p = 0.046), with a diagnostic accuracy of 92%. miR-145-5p expression in nipple fluid differs for intraductal papillomas and breast tissue without abnormalities and, therefore, has potential as a diagnostic marker to signal presence of papillomas in PND patients. However, further refinement and validation in clinical trials are necessary to establish its clinical applicability.

Successful definitive radiation treatment of refractory canine oral papillomatosis.

This case report describes a three-year-old male intact border collie diagnosed with canine papillomavirus type 1 (CPV-1+) oral papillomas resistant to standard-of-care. With time, he developed lesions consistent with squamous cell carcinoma. Malignant tumors were incompletely excised and treated with definitive external beam radiation therapy (45 Gy, 3 Gy × 15 daily). The remaining oral cavity received 27 Gy (1.8 Gy x 15 daily) to treat the disseminated oral papillomatosis. A temporary treatment delay of 2 weeks was instituted due to grade 3 mucositis. The patient remained in complete remission after 10 months from radiotherapy. No tumor recurrences were noted by the owners after >1 year from treatment.

[Advances in the use of bevacizumab for the treatment of respiratory papilloma].

Respiratory papilloma is a relatively common benign tumor of the respiratory tract, and a few patients may develop malignant changes. The disease has an insidious onset and lacks specific clinical manifestations, and its manifestations are closely related to the growth mode, location and size of the tumor. It can involve multiple parts, such as the larynx, trachea, bronchus, and lung parenchyma, which cause coughing, hoarseness, dysphonia, and, in severe cases, may lead to obstruction of the respiratory tract. At present, the treatment of respiratory papilloma lacks standardization, and there is no effective method to cure the disease. Surgery remains the main treatment for alleviating patients' symptoms and preventing airway obstruction. However, due to the high recurrence rate of respiratory papilloma, multiple surgeries are often needed, which reduces the quality of life of patients and increases their disease burden and economic burden. Bevacizumab, a vascular endothelial growth factor-binding antibody inhibitor, is a promising adjuvant treatment modality that shows good potential for reducing symptoms and the frequency of surgery. This article aimed to review the efficacy and safety of bevacizumab for the treatment of respiratory papilloma and discuss the differences and efficacy of the systemic application and intralesional injection of bevacizumab for the treatment of respiratory papilloma.

THE INFLUENCE OF THE DEMODEX MITE ON THE MORPHOLOGICAL PICTURE OF EYELID PAPILLOMA.

The aim of work is description of new observations related to the participation of demodex in tumor morphogenesis with goal to study the example of eyelid papilloma, imagine the connection between the presence of the demodex mite and certain changes in the typical histomorphological picture of the neoplasm. MATERIALS AND METHODS: Histomorphological examination covers biopsy and operative material of eye pathology with diagnosis of neoplasm (eyelid papilloma and actinic keratosis (senile keratosis, senile keratoma, solar keratosis)) were selected, with special attention paid to the presence of horn cysts. Agile methodologies were employed to manage the research workflow effectively. RESULTS: As a result of the conducted histomorphological examination, in 24 cases (48%), patterns pathognomonic for demodectic infection were found. Such patterns, which could indicate the presence of a demodex mite, were cystic formations, as well as fragments of a dead parasite. We noted their presence not only in the tumor tissue, but also in the adjacent hair follicles, sebaceous glands, and subepidermal stroma. It is no coincidence that the authors who previously noted the presence of pigmented elements in keratopapillomas or seborrheic keratomas could not explain their origin, resorting to putting forward such fantastic assumptions as the presence of "symbiosis of melanoblasts and epithelial cells, which ensures the transfer of pigment from the first to the second". CONCLUSIONS: Histomorphological study of serial sections allows us to see the successive stages of transformation of cavity intratissue defects created by the activity of the mite into horn cysts. Cavity defects are the main evidence of demodectic infestation. They occur in basal cell and squamous cell carcinomas, xanthomas, sebaceous adenomas, etc. tumors of the eyelids, but only in keratoacanthomas and senile keratomas they can turn into corneal cysts, which can be assumed to be due to the differentiating potential of these neoplasms.

[Epidemiological features papillomatosis of the larynx in adults: a literature review]. / Epidemiologicheskie osobennosti papillomatoza gortani u vzroslykh (obzor literatury).

The literature review presents current data on the epidemiology, drug, and surgical treatment of laryngeal papillomatosis in adults. Possible prospects for further study of the prevalence and incidence of the disease and provoking factors of recurrence of the disease for the development of possible preventive measures are considered.

[Epidemiological features of laryngeal papillomatosis in adults in Moscow]. / Epidemiologicheskie osobennosti papillomatoza gortani u vzroslykh v Moskve.

OBJECTIVE: To evaluate the incidence of laryngeal papillomatosis (LP) and LP recurrence in adults and to determine the risk factors for the development of LP recurrence in adults in Moscow. To solve the tasks set, a survey of patients carried out, including the collection of complaints and anamnesis, a standard examination of the ENT organs, an assessment of the condition of the larynx, and a histological examination. MATERIAL AND METHODS: We conducted a retrospective analysis of the case histories of 299 patients with LP observed and treated at the Sverzhevsky Research and Clinical Institute of Otorhinolaryngology in the period 2010-2020. RESULTS: On average, over the entire study period, the prevalence of PG was 17.80%. It was found that out of 299 patients, 69.6% (n=208) had a relapse of LP. Papilloma of the larynx were more often localized in the glottis. 275 (92%) patients had a widespread form of LP. LP recurrences were significantly more common in women and in patients with an existing cicatricle process in the larynx. The relapse rate was higher in non-smokers (73.5% vs 47.8%; p<0.001). Although the recurrence rate was higher in patients with non-voice occupations (70.6% vs. 52.9%), there was no statistically significant association between relapses and the vocal professions (p=0.125). CONCLUSION: As a result of the study, a number of risk factors for laryngeal papillomatosis recurrent have been identified, and their study should be continued.

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.

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 TGFß 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.