Immunological tolerance of low-risk HPV in recurrent respiratory papillomatosis

Abstract

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: Th1/Th2 cells; killer immunoglobulin-like receptors (KIR); tumor immunology; vaccination; viral.

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⁺CD127^lowFOXp3⁺ T‐reg cells