Human papillomavirus-driven immune deviation: challenge and novel opportunity for immunotherapy

Abstract

It is now recognized that the immune system can be a key component of restraint and control during the neoplastic process. Human papillomavirus (HPV)-associated cancers of the anogenital tract and oropharynx represent a significant clinical problem but there is a clear opportunity for immune targeting of the viral oncogene expression that drives cancer development. However, high-risk HPV infection of the target epithelium and the expression of the E6/E7 oncogenes can lead to early compromise of the innate immune system (loss of antigen-presenting cells) facilitating viral persistence and increased risk of cancer. In these circumstances, a succession of interacting and self-reinforcing events mediated through modulation of different immune receptors, chemokine and cytokine responses (CCL20; CCL2; CCR2; IL-6; CCR7; IL-12) further promote the generation of an immune suppressive microenvironment [increased levels of Tregs, Th17, myeloid-derived suppressor cells (MDSCs) and PD-L1]. The overexpression of E6/E7 expression also compromises the ability to repair cellular DNA, leading to genomic instability, with the acquisition of genetic changes providing for the selection of advantaged cancer cells including additional strategies for immune escape. Therapeutic vaccines targeting the HPV oncogenes have shown some encouraging success in some recent early-phase clinical trials tested in patients with HPV-associated high-grade anogenital lesions. A significant hurdle to success in more advanced disease will be the local and systemic immune suppressive factors. Interventions targeting the different immunosuppressive components can provide opportunity to release existing or generate new and effective antitumour immunity. Treatments that alter the protumour inflammatory environment including toll-like receptor stimulation, inhibition of IL-6-related pathways, immune-checkpoint inhibition, direct modulation of MDSCs, Tregs and macrophages could all be useful in combination with therapeutic HPV vaccination. Future progress in delivering successful immunotherapy will depend on the configuration of treatment protocols in an insightful and timely combination.

Keywords: T regulatory cells (Tregs); anogenital cancer; cytotoxic T lymphocytes (CTLs); immune-checkpoint inhibitors; myeloid-derived suppressor cells (MDSCs); oropharyngeal cancer; therapeutic HPV vaccines; tumour microenvironment.

Figure 1.

The early events which lead to initial immune deviation and further cascades of self-reinforcing events promoting immune escape and lesion progression to cancer: (1) E6/E7 driven loss of CCL20, loss of Langerhans cells; (2) STAT3 activation in human papillomavirus-transformed cells; (3) IL-6 driven CCL2/CCR2 feedback loop promoting myelo-monocytic infiltration; (4) IL-6-driven fibroblast production of CCL20 attracting Th17, sustaining chronic inflammation; (5) IL-6-driven downregulation of antigen-presenting cell migration and IL-12 production blocking; (6) sustained levels of immune-suppressive and tumour-promoting local factors (macrophages and dendritic cells: local MMP-9 production, Tregs and myeloid-derived suppressor cells (MDSCs); (7) immune-factor-driven up-regulation of PD-L1 by tumour or associated immune cells can block antitumour-specific T-cell effectors. The benefits of HPV oncogene vaccination may only be realized if used in combination with standard of care with or without treatments to overcome the local inflammation. These could include toll-like receptor stimulation (dsRNA), STAT3 and possibly IL6 inhibition, immune-checkpoint (PD-1/PD-L1) inhibition, as well as other strategies to directly modulate local tumour MDSCs, Tregs and macrophages.