Papillomavirus Immune Evasion Strategies Target the Infected Cell and the Local Immune System

Abstract

Persistent infection with human papillomavirus (HPV) initiates ~5% of all human cancers, and particularly cervical and oropharyngeal cancers. HPV vaccines prevent HPV infection, but do not eliminate existing HPV infections. Papillomaviruses induce hyperproliferation of epithelial cells. In this review we discuss how hyperproliferation renders epithelial cells less sensitive to immune attack, and impacts upon the efficiency of the local immune system. These observations have significance for the design of therapeutic HPV cancer immunotherapies.

Keywords: E7 oncoprotein; HPV-associated cancers; HPV16; cancer immunotherapy; cervical cancer; human papillomaviruses (HPVs); immune evasion; therapeutic vaccine.

Figure 1

The key intrinsic immune evasion mechanisms exploited by HPV oncoproteins in keratinocytes (KCs). (A) High-risk HPV E6 and E7 recruit histone modifying enzymes (EZH2, HDAC1, and JARID1B) and DNA methylation enzyme (DNMT1) to suppress TLR9 and CXCL14 transcription. E6 and E7 also bind to the adapter protein STING and ubiquitin ligase E6-AP, leading to downregulation of cGAS–STING cytosolic DNA sensing system and degradation of pro-IL-1β. (B) High-risk HPV E6 and E7 block pathogen recognition receptors (PRR) signal transduction cascades by upregulating the deubiquitinating enzyme Ubiquitin C-Terminal Hydrolase L1 (UCHL1) to inhibit TNF-receptor-associated factor 3 (TRAF3) activation, and by binding to interferon regulatory transcription factor (IRF) to prevent its transcriptional activity in the nucleus. E6 an E7 also interfere with IFN-α/β receptor (IFNAR) signaling pathway by binding to tyrosine kinase 2 (TYK2) to hamper phosphorylation of STAT1 and STAT2, and by interacting with IRF9 to prevent its binding to phosphorylated STAT1 and STAT2 for activating IFN-stimulated genes. (C) High-risk HPV E6 and E7 prevent the nuclear translocation of NF-κB via upregulation of UCHL1. E6 and E7 are also capable of binding to P300/CBP-associated factor (PCAF), a coactivator of NF-κB in the nucleus, thereby downregulating the NF-κB signaling pathway. (D) High-risk HPV E7 can interact with the major histocompatibility complex (MHC) I promoter, leading to repression of MHC I, LMP2, and TAP1 gene. In contrast, E5 reduces MHC I and CD1d expression by blocking the transport of MHC I and CD1d proteins to the cell surface via its interactions with host proteins in the Golgi complex and ER.

Figure 2

Crosstalk between keratinocytes (KCs) and immune cells orchestrates immunosuppression in HPV-associated tumor microenvironment. (A) Downregulation of the chemokine CCL20 and cell adhesion molecule E-cadherin in HPV-infected KCs reduces Langerhans cells (LCs) infiltration in HPV-associated tumor. LCs and migratory dendritic cells (DCs) in tumor microenvironment also display immature or regulatory phenotypes and have reduced migratory capacity to secondary lymphoid tissue, characterized by downregulation of MHC II, CD80, CD86, and the chemokine receptor CCR7, and upregulation of indoleamine 2, 3-dioxygenase 1 (IDO1). This is probably mediated by tumor cell-derived immunosuppressive factors, such as IL-10, TGF-β, IL-6, and prostaglandin E2 (PGE2). (B) Upregulation of tumor-derived factors and downregulation of type I IFNs in HPV-associated tumor suppress NK cell activation and its killing capacity against tumor cells. On the other hand, downregulation of CD1d on KCs dampens NKT cell activity. CD1d^hi myeloid cells in tumor environment might contribute to an alternative source of CD1d, leading to the activation of immunosuppressive IFN-γ-producing NKT cells. (C) The accumulation of tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) is mediated by a variety of tumor-derived factors, such as the chemokine CCL2, macrophage colony-stimulating factor (M-CSF), IL10, TGF-β, IL6 and PGE2. Additionally, Th2-associated cytokines promote TAM differentiation by inducing a phenotypic switch from M1 to M2. TAMs produce Th2-associated cytokines to promote Th2 cell differentiation, and secret the chemokine CCL22 to recruit Tregs. Similarly, MDSCs inhibit the effector immune response by producing a broad range of suppressive molecules, such as arginase 1 (Arg-1), inducible nitric oxide synthase (iNOS), IDO, reactive oxygen species (ROS), IL10, TGF-β, and PD-L1. (D) Tumor-derived factors promote the accumulation of Tregs and a shift from a Th1 toward a Th2 response in local microenvironment. In addition, the recruitment of Th17 cells is increased by CCL20 secretion in cancer-associated fibroblasts (CAFs). Collectively, these modulated responses might in part contribute to downregulation of CTL responses.