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Clinical and Experimental Immunology logoLink to Clinical and Experimental Immunology
. 2019 Oct 31;199(2):131–142. doi: 10.1111/cei.13387

Immunological tolerance of low‐risk HPV in recurrent respiratory papillomatosis

R Ivancic 1, H Iqbal 2, B deSilva 2, Q Pan 3, L Matrka 2,
PMCID: PMC6954675  PMID: 31628850

Summary

Recurrent respiratory papillomatosis (RRP) is characterized by benign exophytic lesions of the respiratory tract caused by the human papillomavirus (HPV), in particular low‐risk HPV6 and HPV11. Aggressiveness varies greatly among patients. Surgical excision is the current standard of care for RRP, with adjuvant therapy used when surgery cannot control disease recurrence. Numerous adjuvant therapies have been used to control RRP with some success, but none are curative. Current literature supports a polarization of the adaptive immune response to a T helper type 2 (Th2)‐like or T regulatory phenotype, driven by a complex interplay between innate immunity, adaptive immunity and HPV6/11 proteins. Additionally, certain immunogenetic polymorphisms can predispose individuals to an HPV6/11‐tolerant microenvironment. As a result, immunomodulatory efforts are being made to restore the host immune system to a more balanced T cell phenotype and clear viral infection. Literature has shown exciting evidence for the role of HPV vaccination with Gardasil or Gardasil‐9 as both primary prevention, by decreasing incidence through childhood vaccinations, and secondary prevention, by treating active RRP disease. Multi‐institution randomized clinical trials are needed to better assess their efficacy as treatment for active disease. Interestingly, a DNA vaccine has recently shown in‐vitro success in generating a more robust CD8+ T cell response. Furthermore, clinical trials for programmed death 1 (PD‐1) inhibitors are under investigation for RRP management. Molecular insights into RRP, in particular the interplay between RRP and the immune system, are needed to advance our understanding of this disease and may lead to the identification of immunomodulatory agents to better manage RRP.

Keywords: killer immunoglobulin‐like receptors (KIR), Th1/Th2 cells, tumor immunology, vaccination, viral


Current literature supports a polarization of the adaptive immune response to a Th2‐like or T‐regulatory phenotype, driven by a complex interplay between innate immunity, adaptive immunity, and HPV6/11 proteins in recurrent respiratory papillomatosis. Additionally, certain immunogenetic polymorphisms can predispose individuals to an HPV6/11‐tolerant microenvironment. As a result, immunomodulatory efforts are being made to restore the host immune system to a more balanced T cell phenotype and clear HPV infection.

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Introduction

Recurrent respiratory papillomatosis (RRP) is a rare, benign, chronic disease that involves exophytic lesions of the mucosa of the respiratory tract 1. During the past two decades, incidence and prevalence have remained relatively consistent across the globe at less than 0·01%, with minor variability between adult and juvenile subpopulations 2, 3, 4, 5. It is most commonly caused by low‐risk human papillomavirus (HPV) types 6 and 11 6. The clinical course of RRP shows variability, with some patients experiencing spontaneous remission for periods of time and others showing aggressive recurrent growth 2. RRP is associated with significant morbidity secondary to airway obstruction and voice change and, on infrequent occasions, mortality or malignant transformation 7, 8. To date, there is no cure for the disease, but the treatment is directed toward symptomatic control and reduction of disease burden 9. The current standard of care for RRP is surgical excision, primarily with microdebriders and lasers, and adjuvant therapies as needed. Patients often require multiple surgeries during their lifetime, sometimes several each year, and less frequently can require tracheotomy or adjuvant drug administration, making RRP an expensive disease to treat 10. Clinical complications can arise from frequent surgical procedures, papillomatous lower airway involvement and therapeutic resistance 11.

Literature supports that juvenile‐onset RRP is transmitted vertically during pregnancy or is acquired at birth from an HPV‐infected mother 12. In contrast, scarce literature is available regarding the acquisition mechanism of adult‐onset RRP. One study showed that risk of adult‐onset RRP is associated with number of sexual partners, although not all studies corroborate this finding 9, 13. Of note, juvenile‐onset RRP has a more aggressive clinical course and a greater potential for airway compromise 14.

A 2017 study by the National Center for Health Statistics (NCHS) of the Centers for Disease Control and Prevention (CDC) examined the prevalence of oral HPV infection in more than 9000 participants aged 18–69 years in the United States 15. They estimated that 14·7% of the study population has detectable HPV DNA in the oral cavity. When separated by genotype, approximately 1% of the population has oral cavity infected with HPV6 or HPV11, yet only a small fraction of those develop RRP 16. Current hypotheses suggest that multiple genes predispose individuals to tolerate HPV6/11 infection. Genetic analyses of RRP patients have revealed an increased frequency of certain human leukocyte antigen (HLA) alleles, as well as a decreased frequency of certain innate immune cell receptors that may predispose individuals to RRP development and be correlated with disease severity 17, 18, 19. When HPV infects the epithelium of susceptible individuals, HPV oncoproteins, predominately E6, can interfere with innate immunity and skew the adaptive immune response to a type 2 T helper cell (Th2)‐like or T regulatory (Treg) cell phenotype. This skewed adaptive immune response, in combination with an altered innate immune response, produces an HPV‐tolerant cytokine microenvironment 20, 21, 22, 23. The aim of this review is to characterize the current understanding of RRP etiology, focusing on immune system tolerance of HPV6/11 in the setting of RRP as well as the current and future immunomodulatory approaches being investigated to manage this disease.

HPV and RRP

HPV structure and infection

The HPV genome is encapsulated in an icosahedral protein structure 55 nm in diameter. Its double‐stranded, circular DNA encodes for eight gene proteins 24. There are six ‘early’ genes (E1, E2, E4, E5, E6 and E7) responsible for cell cycle disruption and two ‘late’ genes (L1 and L2) that encode capsid proteins. E1 and E2 control viral gene replication and expression, while E4 releases the virus from its host cell. E5, E6 and E7 are responsible for tumor formation and malignancy 24.

HPVs are known for causing benign and malignant anogenital lesions as well as cutaneous warts; however, they can also infect the epithelium of the head and neck, including ocular conjunctiva, ear canal, nasal sinuses, oral cavity, tonsils, pharynx and larynx. When low‐risk HPV6/11 infection leads to papilloma formation in the larynx, it is called RRP 25. Adult‐onset RRP is most probably associated with orogenital spread of HPV; the leading risk factor for juvenile‐onset RRP is a maternal history of genital papilloma and vertical transmission from mother to child during childbirth 26, 27. HPV infects basal epithelial cells in the larynx and usually occurs via membrane disruption 28, 29. The mechanism of infection in the basal epithelium of the vocal folds is relatively unknown, but it is hypothesized that microtrauma from vocalization may be a mode of entry 30, 31. In general, after infection, HPV DNA can integrate into the host genome, or it can exist in the episomal form, with its circular double‐stranded DNA intact. In RRP, HPV DNA is maintained in the episomal state within the nucleus 32. Entry of the HPV genome into the basal cell nucleus requires mitosis, which then allows cell proteins to interact with the HPV genome and activate viral protein transcription. Viral oncoproteins E6 and E7 target the tumor suppressors p53 and pRB, respectively, induce cell division and promote differentiation of HPV‐infected basal cells into upper epithelial layers 33, 34. In‐situ hybridization shows HPV6/11 RNA expression to be strongest in the suprabasal layer of the epithelium 35. There is some evidence that the laryngeal squamo–columnar epithelial junction is more vulnerable to HPV infection than squamous epithelia due to the absence of the protective, non‐dividing outer squamous layers 25. Tracheal papilloma involvement may be aided by metaplastic squamous changes of the trachea permitting HPV infection; however, HPV has also been shown to directly infect tracheal ciliated columnar epithelium 36. Additionally, there is evidence that co‐infection with human immunodeficiency virus (HIV) proteins tat and gp120 may disrupt epithelial tight junctions, facilitating HPV entry and potentiating HPV‐associated lesions 37. Concurrent or co‐infection with herpes simplex virus‐1, cytomegalovirus or Epstein–Barr virus has also been shown in both juvenile and adult RRP patients and may be predictive of an aggressive clinical course 1, 38, 39.

The reason for recurrence of RRP is still not well understood. Some hypothesize that it is due to repeated reinfections with novel variants of HPV, while others point to evidence of persistent infection from latent HPV in nearby ‘normal’ epithelial tissue 40. Kocjan et al. reported that the HPV genome of 67 of 70 (95·7%) patients showed complete genetic identity between either the highly variable regions (LCR, E5a) of the genetic code or between entire HPV genomes from the initial HPV isolate and a second isolate obtained 1–22 years later 40. This observation indicates that the HPV genome is genetically stable and does not change during the course of the disease, suggesting that disease recurrence may be caused by reactivation of latent HPV in adjacent normal epithelia 40. Moreover, it has been suggested that adjacent tissue may provide a reservoir for the latent virus and wait for trigger signals. For example, the healing process after surgical removal of papillomas may promote the reactivation and replication of latent viruses in the surrounding tissue 25, 41, 42. Another study showed that exposure to acid or gastric enzymes may cause epithelial irritation, producing an inflammatory response and contributing to the spread or recurrence of RRP 43. Therefore, controlling gastroesophageal reflux may assist in the management of RRP 44, 45, 46, 47.

Pathogenesis in larynx

HPV6/11‐infected laryngeal papilloma cells exhibit an altered cellular biology. E6 and E7 are the most important HPV proteins in pathogenesis and interfere with tumor suppressors p53 and pRb, respectively, as well as several other proteins involved with cell cycle regulation, proliferation and apoptosis 48. Furthermore, laryngeal papilloma cells over‐express epithelial growth factor receptor (EGFR) and contain multiple altered EGFR‐dependent signaling pathways, including elevated phosphatidylinositol 3‐kinase (PI3K) activity 49. Cyclo‐oxygenase‐2 (COX2), a normal mediator of inflammation, is also over‐expressed in papilloma cells and has been shown to inhibit epithelial differentiation and apoptosis. Wu et al. showed that COX‐2 over‐expression is mediated by EGFR‐dependent Rac1 over‐expression, a Rho family GTPase that controls cell cycle progression, apoptosis, gene expression, cell motility and tumor invasiveness 50, 51. Additionally, in‐vitro inhibition of COX‐2 in papilloma cells with the selective COX‐2 inhibitor celecoxib showed reduced cell growth and increased apoptotic activity 50. Contrary to these data, a randomized double‐blind controlled study was recently completed that assessed the safety and efficacy of celecoxib in both pediatric and adult RRP patients (NCT 00571701). The primary objective of this trial was to determine the efficacy of celecoxib in comparison to conventional endoscopy and surgical treatment. The data showed that celecoxib did not affect the mean percentage change in papilloma growth rate during treatment compared to baseline (P = 0·57). It should be noted that the study celecoxib dose was reduced by regulators to a dose lower than that typically administered because of concerns for cardiac side effects.

High‐ versus low‐risk HPVs

HPV subtypes are stratified into low‐ and high‐risk groups based on their oncogenic potential; however, this does not mean that low‐risk HPV subtypes cannot also cause cancer. While both low‐ and high‐risk HPVs infect and replicate in the same cellular environments and overcome the same cellular defenses, it is interesting that their respective pathologies and cellular targets differ markedly. Much less is known about the function of low‐risk HPV proteins than those of high‐risk HPV types, and RRP is almost exclusively caused by low‐risk HPV6 and HPV11 52. Research has shown that the E7 protein from HPV6 and HPV11 has a lower binding affinity to pRb than the E7 protein from high‐risk HPV types, which may be one reason that HPV6 and HPV11 are less efficient at malignant transformation 48, 53. In addition, E7 from high‐risk strains induce proteasome‐mediated degradation of pRb, freeing E2F transcription factor to stimulate cells into S phase, and only high‐risk E6 can degrade p53 in an E6AP‐dependent manner, compromising host cell ability to complete cell cycle checkpoints 54. E6 from both high‐ and low‐risk HPV strains can bind to p300/CBP to prevent acetylation of p53, but high‐risk E6 has a higher binding affinity to p300/CBP than low‐risk E6 55, 56, 57.

HPV 6 versus 11

Between the two low‐risk types, a more aggressive clinical course of RRP is associated with HPV11 lesions 58. This includes diagnosis at a younger age, need for more surgeries per year and decreased remission rate. Gerein et al. evaluated the use of interferon (IFN)‐α in the treatment of JO‐ and AO‐RRP caused by both HPV6 and HPV11 59. For HPV6‐positive patients, 16 of 17 (94%) had remission after treatment, and 11 of 17 (65%) maintained remission during a follow‐up of a mean 172 months. In the HPV11‐positive patients, only four of 14 (29%) showed remission after treatment, and two of 14 (14%) maintained remission. Therefore, HPV6‐positive RRP was more responsive to IFN‐α therapy and was less likely recur during the follow‐up period than HPV11‐positive RRP. The severity score for RRP aggressiveness was also significantly higher in HPV11‐positive than in HPV6‐positive patients 59. There is limited literature on the oncogenic differences between HPV6 and HPV11. First, HPV11 E6 and E7 could have more ‘oncogenic’ targets than HPV6 or be more efficient at interacting with host cell proteins. Vambutas et al. proposed that HPV11 E7 inhibits ATP‐dependent peptide transport due to interaction with TAP‐1, the protein that transports peptides into the endoplasmic reticulum for presentation by major histocompatibility complex (MHC) class I 60. Furthermore, it has been hypothesized that HPV11 E7 interacts more strongly with TAP‐1 than HPV6 E7, leading to decreased immune responsiveness and the more aggressive disease course observed in HPV11 RRPs 61. Secondly, subtle life cycle differences may make HPV11 more oncogenic than HPV6. Peh et al. showed that the life cycles of low‐risk HPV11 and high‐risk HPV16 were organized similarly. Both their sequence of viral gene expression and pattern of viral genome amplification in the epithelium were closely related, suggesting a closer association between HPV11 and HPV16 than previously thought 62.

RRP and malignancy

Approximately 2% of patients with RRP develop a carcinoma in the region of the papilloma 52. In the above‐mentioned Gerein et al. study evaluating IFN‐α in the treatment of juvenile and adult RRP there were no cases of malignancy in HPV6‐positive patients, but five of 14 (36%) of the HPV11‐positive patients developed malignancy in the area of the papilloma at some point during the 20‐year follow‐up. This study provides further evidence that HPV11 leads to a more severe clinical course and a higher rate of malignant transformation 59. It should be noted that this study included only patients with RRP disease that was aggressive enough to require adjuvant therapy, so a higher malignancy rate would be expected in this study versus reality. A case–series of three children with HPV11‐induced RRP who developed bronchogenic squamous cell carcinoma provided evidence that HPV11‐induced RRP may undergo malignant transformation 58, 63, 64, 65. In rare instances, RRP can be aggressive enough to cause lung involvement, and many of these cases result in lung cancer. Interestingly, HPV genome analysis in these patients reveal substantial mutations; specifically, amplification of regions that promote increased expression of HPV E6 and/or E7. This suggests that even low‐risk HPVs can cause malignant transformation under the right circumstances 66. In addition, two separate cohort studies found that a history of tobacco use was not a risk factor for dysplasia or malignancy in RRP 7, 67.

There is also evidence that low‐risk HPVs can modify cellular processes such as that seen in some malignancies. Chemokine (C‐X‐C motif) ligand (CXCL)1, CXCL6, CXCL8 and vascular endothelial growth factor (VEGF)‐A are differentially expressed in papillomas and associated with malignancy, operating as growth and angiogenic factors 68. Microarray analysis revealed that CXCL1, CXCL6 and VEGF‐A were significantly correlated with severe RRP, providing evidence that angiogenesis is integral to disease pathology 69. They also identified reduced expression of certain tumor suppressors; namely, insulin‐like growth factor‐binding protein (IGFbp5), four‐and‐a‐half LIM domains 1 (FHL1) and SPARC‐like 1 (mast9, hevin) (SPARCL1), and over‐expression of several proto‐oncogenes, including IGFbp3, placental growth factor (PGF), and parathyroid hormone‐like hormone (PTHLH) 69. Three members of the S100 family, which have both oncogenic and tumor‐suppressive functions, were also differentially expressed in papillomas 69.

Immunology

Studies have shown that RRP patients can mount an initial, measurable serum antibody response to both HPV6 and HPV11, indicating that there is viral immune recognition in these patients 70, 71, 72. Thus, immune dysfunction in RRP is suggestive of HPV6/11 tolerance, not a lack of viral recognition 20. Interestingly, RRP patients have demonstrated normal immunological responses to other pathogens without chronic disease manifestations, indicating a site‐specific immune tolerance of HPV6/11 that does not necessarily apply to other mucosal sites 20, 73. Therefore, it is hypothesized that RRP is a multi‐gene disease that polarizes innate and adaptive immunity to tolerate chronic and local HPV6/11 infection (Fig. 1).

Figure 1.

Figure 1

Summary of low‐risk HPV6/11 and immune system dysfunction in RRP. This schematic highlights the proposed defective innate and adaptive immune responses to HPV‐infected keratinocytes to tolerate chronic, low‐risk HPV6/11 infection in RRP patients. Innate immunity is in the top half and adaptive immunity is in the bottom half. A blood vessel is included for peripheral blood immunity findings. Cytokines that are downregulated are in red, while cytokines that are upregulated are in green. M⌀ = macrophage; iLC = immature Langerhans cell; IL = interleukin, IFN = interferon; Tfh = T follicular helper cell; T‐reg = T regulatory cell.
  1. TAP‐1 polymorphisms in ATPase domain
  2. MHC Class I expression is downregulated for an unknown reason, so there is less antigen presentation for NK cell‐ and CD8+ cytotoxic T cell‐mediated killing
  3. Less HPV‐specific cytotoxic T cell killing due to MHC Class I downregulation
  4. MHC Class II complexes present E2 and E6 peptides; however, E6 is the dominant inducer of the Th2‐like phenotype in RRP
  5. iLCs have decreased response to the proinflammatory IL‐36‐γ
  6. KIR genes 3DS1 and 2DS1 are protective against severe disease
  7. Papillomas are enriched for CD8+CD28 T cells that expressed the Th2‐like cytokines IL‐10 and TGF‐beta
  8. MHC Class II alleles: DRB1*0102, DRB1*0301, DQB1*0201, DQB1*0202 skew to Th2‐like phenotype; DQB1*0602 may be protective
  9. Naïve CD4+ T cells are induced predominately to a Th2‐like or T‐reg phenotype either directly by HPV proteins or indirectly by iLCs, which then overproduce Th2‐like cytokines
  10. CD4+CD25+CD127lowFOXp3+ T‐reg cells

Innate and adaptive immunity

Recent studies have shown that HPV may be a part of the commensal microflora of primary epithelial cells, and approximately 1% of the population harbors HPV6/11 DNA in the larynx 15. However, a very small percentage of HPV‐exposed individuals develop RRP 16, 74. This suggests that altered immune function may contribute to the development of RRP. However, it is unclear why some individuals do not mount a sufficient anti‐HPV response to the initial HPV6‐ and HPV11‐infected keratinocytes 75. One study showed that the number of CD4+ T helper cells, CD8+ cytotoxic T cells, B cells and natural killer (NK) cells was similar between healthy individuals and RRP patients 76. That same group later reported that RRP patients have increased numbers of a specific subset of circulating CD4+ T cells that express Th2‐like cytokines; therefore, the adaptive immune response in patients with RRP becomes polarized towards a Th2‐like or T regulatory (Treg) phenotype 20. Antigen‐presenting cells (APCs), including polarized macrophages and immature Langerhans cells (iLCs) and naive T cell‐derived cells, namely Th2‐like and Treg cells, drive this in response to HPV proteins 20. HPV E6 protein is the dominant inducer of immune dysregulation in RRP 21. In fact, there is evidence that E6 can directly inhibit IL‐2 and IL‐18 expression, two cytokines that contribute to maintaining a balanced adaptive immune response and an HPV‐specific cytotoxic T cell function 21, 77. Polarization towards a Th2‐like phenotype up‐regulates the Th2 effector cytokine IL‐10. IL‐10 suppresses Th1 cells that aid in clearing viral infection via production of cytokines such as interferon (IFN)‐γ, IL‐2 and tumor necrosis factor (TNF)‐α 20, 78. In support of this observation, several studies have shown that levels of the Th2‐like chemokines CCL17, CCL18 and CCL22 were found to be high in the serum of patients with RRP 22, 79. Over‐expression of these cytokines is correlated with RRP disease severity, and may provide biomarkers for predicting disease prognosis 23. Another study suggested that RRP patients have more circulating CD4+ T cells that constitutively express the Th2‐like cytokines IL‐4 and IL‐10 20, 80. Treg cells [CD4+CD25+CD127lowforkhead box protein 3 (FoxP3+)] were also enriched in papilloma samples compared to autologous peripheral blood mononuclear cell (PBMC) samples, indicating that Treg cells may contribute to immune dysfunction 81. Furthermore, the HPV‐specific effector CD8+ T cell population and its killing function is altered in RRP, possibly to a more immature or Th1 suppressor function. One study found that papillomas were enriched for CD8+ CD28 T cells that expressed the Th2‐like cytokines IL‐10 and TGF‐β and were correlated with disease severity 82. Because LCs are required for microbial‐specific CD8+ T cell development, Devoti et al. hypothesized that deficient LC production of IL‐12 and CCL1 could explain the loss of CD8+CD28 T cell response to HPV‐infected cells and reduced IFN‐γ expression 83. Immunoglobulin (Ig)G levels were also found to be extremely low in JO‐RRP patients compared to healthy controls, and B cell maturation and antibody production were limited in these patients, due possibly to reduced IL‐21 secretion by T follicular helper (Tfh) cells 84.

Innate immunity has also been shown to be altered in the RRP microenvironment. In fact, dysfunctional activation of adaptive immunity by macrophages and dendritic cells (Langerhans cells) in the papilloma microenvironment may perpetuate the polarization to a Th2‐like phenotype, suppressing HPV clearance. Memory Th2‐like T cells expressing IL‐4, IL‐10 and TGF‐β alternatively activate macrophages to express the Th2‐like chemokines CCL17 and CCL18, which polarize naive CD4+ T cells to become memory Th2‐like T cells and Tregs 19. This is because HPV6/11 E6 has been shown to reduce the expression in papilloma of IFN‐γ, a Th1‐like cytokine which normally balances macrophage activation 21. Immature dendritic cells also contribute to a Th2‐like T cell response via production of CCL18 and low baseline expression of CCL1 83. IL‐12 and IL‐18, constitutively expressed by dendritic cells to support Th1‐like T cell maturation and IFN‐γ expression, were also deficient in severe RRP cases 21. Another study found that iLCs in RRP patients have a decreased response to the proinflammatory cytokine IL‐36‐γ, further contributing to an ineffective adaptive immune response to HPV 83. Additionally, polymorphic killer‐cell immunoglobulin‐like receptors (KIRs) on NK cells may aid in the early clearance of HPV6/11 infection, and their absence may be positively correlated with RRP disease severity 17, 18. Furthermore, one group used microarray analysis to identify genes that may contribute to RRP etiology by measuring changes in the transcriptional profiles between papilloma tissue and autologous laryngeal epithelium 69. They found elevated expression of IL‐1F9, which was strongly correlated with severe RRP and may alter innate signaling to stimulate a Th2‐like response 69, 85. Their data also corroborate that the papilloma microenvironment contains an expression profile consistent with an altered innate immune response and defective Th1‐like response. They found that mRNA expression was decreased for the Th1‐like chemokines CCL19 and CCL21 and elevated for the Th2‐like chemokine CCL20 23. Interestingly, a different study by the same group found that CCL20 was only differentially over‐expressed in the basal cell layer. They hypothesized that CCL20 expression in these cells may form a barrier, selectively admitting Th2‐like T cells and restricting access to more superficial epithelial layers, where HPV expression is greatest 23.

Recent research is exploring the role of immune inhibitory receptors in HPV tolerance and RRP development. Programmed death ligand 1 (PD‐L1), a negative immune regulator found on APCs, was shown to be up‐regulated in both papilloma and infiltrating immune cells 86, 87. Furthermore, T cell immunoglobulin and ITIM domain (TIGIT), another immune inhibitory receptor, has been found on Treg cells in papilloma tissue (personal communication, 10 October 2019) 88. These findings may show how direct down‐regulation of the immune system allows for persistent HPV infection and the development of RRP.

Immunogenetics

There is evidence that multiple genes may predispose individuals to the development of RRP from HPV infection and explain varying disease severity among the RRP population. RRP patients have an increased frequency of HLA class II alleles DRB1*0102, DRB1*0301, DQB1*0201 and DQB1*0202, associated with reduced IFN‐γ expression. Alternatively, DQB1*0602 may be protective in RRP patients 19. Single nucleotide polymorphisms in the TAP‐1 gene have also been correlated with disease severity, and this severity may be mitigated by the proximity of the TAP‐1 gene to HLA class II genes 61. In addition, KIRs control early NK cell response against viral infection and tumor transformation. Bonagura et al. showed that the absence of select KIR genes 3DS1 and 3DS2 may be predictive of disease severity, and reactivating them in 3DS1‐ and 3DS2‐deficient patients may decrease RRP aggressiveness 17, 18. These findings may explain why certain patients are predisposed to defective clearance of HPV‐infected keratinocytes.

Collectively, these findings provide initial insight toward the intricate interaction between the immune system and low‐risk HPV. Additional research is critically needed to expand our understanding of immune system dysfunction in RRP, enabling the rational development of immunomodulatory approaches to better manage RRP patients.

Immunomodulatory therapies

Surgery is the primary treatment modality to manage RRP, and adjuvant therapy is required when surgery cannot control the disease. Early attempts at immunological therapies were directed at the use of IFN‐α, with some promising results. However, systemic side effects of IFN‐α have limited its use, and adjuvant therapies have moved toward intralesional bevacizumab, a monoclonal humanized antibody against the angiogenic factor VEGF‐A, and cidofovir, a cytosine nucleotide that blocks viral DNA polymerase. However, these are still not curative, so immunomodulatory efforts are being made to restore host immune function and clear HPV infection.

HPV vaccine

Vaccination has the most exciting potential to manage RRP. The quadrivalent vaccine Gardasil, with activity against HPV subtypes 6, 11, 16 and 18, and the new nonavalent vaccine Gardasil‐9, with activity against HPV subtypes 6, 11, 16, 18, 31, 33, 45, 52 and 58, were developed from the HPV L1 viral capsid protein as a primary prevention measure to prevent healthy patients from initial HPV infection or infected patients from reinfection 43. Its efficacy in reducing RRP incidence through herd immunity was demonstrated in Australia in 2007, when an extensive Gardasil vaccination program was initiated for females aged 12–26 years and a school‐based program that provided Gardasil to boys and girls aged 12–13 years. A prospective study of the Australian juvenile RRP population showed a decline in incidence rate from 0·16 per 100 000 in 2012 to 0·022 per 100 000 in 2016 [95% confidence interval (CI), P < 0·001]. Furthermore, male genital warts declined, suggesting that herd vaccination effects may be decreasing horizontal transmission 89. These data suggest that juvenile‐onset RRP may be a vaccine‐preventable disease. Currently, the Centers for Disease Control’s (CDC) Advisory Committee on Immunization Practices (AICP) recommends the use of Gardasil‐9 for girls aged 13–26 and boys aged 13–21, but some health insurance policies may even cover HPV vaccination for older adults 90.

A systematic review of HPV vaccination as secondary prevention for active RRP disease found that nine of 12 (75%) studies reported decreased disease recurrence, decreased disease burden or increased intersurgical interval after adjuvant treatment with HPV vaccine 91. Tjon Pian Gi et al. reported, in a group of RRP patients, that antibody activity against their particular HPV type rose significantly when comparing pre‐ and post‐Gardasil vaccination serologies (< 0·001) 92. Furthermore, anti‐HPV IgG titers were found in cord blood samples of Gardasil‐vaccinated pregnant women, demonstrating that anti‐HPV antibodies cross the placenta 93. These data suggest that Gardasil vaccination may be viable as both a prophylactic and therapeutic treatment regimen; however, multi‐center randomized controlled trials are needed to fully assess the efficacy of the HPV vaccination as a therapeutic vaccine in the RRP population.

One explanation for the therapeutic successes of L1 viral capsid vaccines, such as Gardasil and Gardasil‐9, in RRP may be related to HPV’s existence in the episomal state within the papilloma cell 32. It has been documented that the integration of HPV DNA into host cell DNA causes deletion of HPV late genes L1 and L2 94. This renders prophylactic vaccines generated with the L1 viral capsid protein ineffective at targeting these cells 95. However, because RRP cells harbor episomal HPV DNA, these late genes are expressed, promoting antigen recognition. This may be one reason why Gardasil and Gardasil‐9 demonstrate some efficacy as a secondary prevention measure in RRP. However, the limitations of protein‐based vaccines are based on their low immunogenicity. They are presented primarily via the MHC class II pathway and mildly via the MHC class I pathway, which generates a strong antibody response, but only a mild cytotoxic T cell response, respectively. This allows for effective antibody‐mediated neutralization and phagocytosis of HPV, but inefficient cytotoxic killing of infected cells. Furthermore, literature supports that certain MHC class II alleles predispose patients to generating a skewed Th2‐like response in RRP, making this route of immunogenicity less likely to be successful in clearing persistent infection.

Unlike preventative vaccines aimed at antibody generation, therapeutic vaccines may have greater therapeutic benefit by generating a more robust cell‐mediated immune response. DNA vaccines, comprised of a plasmid encoding HPV E6 and E7 proteins, generate a more sustained immune response than capsid protein vaccines through continuous expression of viral antigens. Dendritic cells are integral in the immunogenicity DNA vaccination, specifically in activating MHC class I‐mediated cytotoxic T cell killing. They may either present exogenous antigens generated from transfected cells or endogenous antigens from direct transfection of dendritic cells 96, 97. Ahn et al. investigated a novel calreticulin‐linked DNA vaccine encoding HPV11 E6 and E7 proteins in mice that were inoculated with HPV11 E6/E7 tumors. Not only did they find a robust CD8+ T cell response, they also showed a reduction in tumor growth and volume 98. As more research works to understand immune‐tolerant microenvironment of RRP, therapeutic vaccination may be an exciting development to restore host immune function and clear HPV infection.

PD‐1 inhibitors

PD‐1 on leukocytes binding to its ligands, PD‐L1 and PD‐L2, on APCs negatively regulates the immune system, and PD‐L1 has been shown to be highly expressed in HPV‐associated head and neck squamous cell carcinoma (HNSCC) 99, 100. Furthermore, PD‐L1 was upregulated in both papilloma and infiltrating immune cells; therefore, the PD‐1/PD‐L1 interaction may contribute to immunosuppression in RRP 86, 87. PD‐1 inhibitors, such as pembrolizumab and avelumab, block the interaction between PD‐1 and its ligands and have clinical efficacy in numerous advanced solid tumors, including HPV‐associated HNSCC 101. The activity against HPV‐associated HNSCC has prompted investigators to initiate a Phase II clinical trial to assess the efficacy of pembrolizumab in RRP (NCT 02632344). RRP patients will be administered 200 mg pembrolizumab as a 30‐min intravenous (i.v.) infusion every 3 weeks on day 1 of each cycle after all procedures and assessments have been completed. Another Phase II clinical trial will assess the efficacy of avelumab in RRP by treating patients with 10 mg/kg avelumab as an i.v. infusion every 2 weeks for up to six total doses (NCT 02859454).

Conclusion

HPV6/11 infection is present in an estimated 1% of the general population; however, only a small subset of infected individuals will develop RRP. There is some evidence that expression of certain HLA alleles may predispose people to develop RRP and may be linked to disease aggressiveness 19. Another study showed that the absence of certain NK cell receptors was positively correlated with RRP severity 18. These are mainly unexplored areas of research in RRP, and certainly a more comprehensive longitudinal study focusing on HPV infection and RRP development would provide more insight on genetic events that predispose an individual to RRP.

The literature suggests that HPV6/11 proteins dampen immune system surveillance of HPV6/11‐infected cells, but the mechanism is unclear. Evidence points toward the polarization of the adaptive immune system to a Th2‐like or Treg phenotype in RRP patients, which subsequently suppresses Th1 cell‐mediated clearance of the infection 20. One group found this polarization to be directed by E6 21. Another study proposed that E7 interferes with viral peptide presentation to adaptive immune cells via an interaction with TAP‐1 60. These preliminary findings suggest an interaction between the immune system and low‐risk HPV proteins. Evidence of a defect in the innate proinflammatory responses showed that NK cells failed to detect and/or lyse HLA class I‐deficient cells, and that macrophages and Langerhans cells failed to initiate a proper adaptive immune response 17, 83. These interactions between low‐risk HPV proteins, innate immune cells and adaptive immune cells perpetuate an immunosuppressive cycle, quelling anti‐HPV function. Further understanding the molecular interactions of low‐risk E6 and E7 proteins with the immune system is necessary to discover how HPV6/11‐infected cells evade immune surveillance. If immune system dysfunction is the major contributing factor to the recurrence of RRP, then immunomodulatory approaches can be tailored to manage RRP patients more effectively.

Currently, the standard of care for RRP patients is surgical excision, with use of intralesional adjuvant therapies as needed and reservation of systemic adjuvant therapies for the most severe cases. Current adjuvants are not curative, so immunomodulatory approaches are under investigation with the goal of clearing HPV infection and preventing recurrence. HPV vaccines, including the newly developed nonavalent Gardasil‐9, have shown benefit as both primary and secondary prevention, but additional work, in particular a multi‐center randomized clinical trial, is needed to evaluate the efficacy of HPV vaccines to manage active disease. Furthermore, there is increasing evidence that widespread HPV vaccination reduces HPV genital wart acquisition and, as a result, secondary laryngeal infections and RRP incidence. Additionally, DNA vaccines stimulate a more robust, cytotoxic CD8+ T cell response, and an in‐vitro study demonstrates reduction in both tumor growth and volume in an HPV11‐driven tumor 98. Due to evidence of PD‐L1 overexpression in both papilloma and infiltrating immune cells, two ongoing Phase II clinical trials have been initiated to assess the efficacy of the anti‐PD‐1 antibodies in RRP.

In conclusion, RRP is a recalcitrant disease, incurable with current treatment modalities. Adjuvant therapies are often utilized to control aggressive disease; however, these treatments are not curative and typically only increase the interval between surgical procedures. Research is accumulating to support the notion that the RRP microenvironment is immunocompromised and, thus, regaining Th1 cell function may be a durable approach to prevent persistent infection. A better understanding of the mechanisms used by HPV6/11 to escape immune surveillance may lead to the development of novel immunomodulatory approaches to manage RRP patients more effectively.

Disclosure

The authors certify that they have no affiliations with or involvement in any organization that has financial or non‐financial interest in the material discussed in this manuscript.

Acknowledgements

The illustration in Figure 1 was created by Anthony S. Baker, CMI, ©The Ohio State University.

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