Immunodiagnosis and Immunotherapeutics Based on Human Papillomavirus for HPV-Induced Cancers

Abstract

Infection with human papillomavirus (HPV) is one of the main causes of malignant neoplasms, especially cervical, anogenital, and oropharyngeal cancers. Although we have developed preventive vaccines that can protect from HPV infection, there are still many new cases of HPV-related cancers worldwide. Early diagnosis and therapy are therefore important for the treatment of these diseases. As HPVs are the major contributors to these cancers, it is reasonable to develop reagents, kits, or devices to detect and eliminate HPVs for early diagnosis and therapeutics. Immunological methods are precise strategies that are promising for the accurate detection and blockade of HPVs. During the last decades, the mechanism of how HPVs induce neoplasms has been extensively elucidated, and several oncogenic HPV early proteins, including E5, E6, and E7, have been shown to be positively related to the oncogenesis and malignancy of HPV-induced cancers. These oncoproteins are promising biomarkers for diagnosis and as targets for the therapeutics of HPV-related cancers. Importantly, many specific monoclonal antibodies (mAbs), or newly designed antibody mimics, as well as new immunological kits, devices, and reagents have been developed for both the immunodiagnosis and immunotherapeutics of HPV-induced cancers. In the current review, we summarize the research progress in the immunodiagnosis and immunotherapeutics based on HPV for HPV-induced cancers. In particular, we depict the most promising serological methods for the detection of HPV infection and several therapeutical immunotherapeutics based on HPV, using immunological tools, including native mAbs, radio-labelled mAbs, affitoxins (affibody-linked toxins), intracellular single-chain antibodies (scFvs), nanobodies, therapeutical vaccines, and T-cell-based therapies. Our review aims to provide new clues for researchers to develop novel strategies and methods for the diagnosis and treatment of HPV-induced tumors.

Keywords: cervical cancer; human papillomavirus; immunodiagnosis; immunotherapeutics; monoclonal antibody.

Figure 1

Human papillomavirus (HPV)-induced cancers in human beings. HPV commonly induced oropharyngeal cancer and esophageal adenocarcinoma (also referred to as head and neck cancer) in the orpharynx and esophagus and cervical cancer, vaginal cancer, vulvar cancer, anal cancer, and penile cancer in the reproductive system.

Figure 2

Schematic view of gene structure of human papillomavirus (HPV) genome. The HPV genome has an early transcribed region encoding six early proteins, including E1, E2, E4, E5, E6, and E7, a late transcribed region encoding two late proteins, including L1 and L2, a non-transcribed region containing the cis-elements necessary for replication and transcription and a small highly variable non-coding region located between E5 and L2. LCR, long control region.

Figure 3

Schematic view of different samples for immunodiagnosis of human papillomavirus (HPV)-induced cancers. Detection of HPV antigen or antibodies was applied for immunodiagnosis in three kinds of sample types, including tumor tissues/cells, exocrine samples, and sera from patients.

Figure 4

Schematic view of the molecular network and functions of human papillomavirus (HPV) E5, E6, and E7 oncoproteins in HPV-induced cancers. E5, E6, and E7 oncoproteins are responsible for the carcinogenesis and tumorigenesis of HPV-induced cancers via activating multiple signaling pathways, such as cell cycle signaling, EGFR pathway, migration, and invasion pathways, p53 pathway and some epigenetic pathway. AKT, AKT serine/threonine kinases; B-MYB, MYB proto-oncogene like 2, MYBL2; CARM1, coactivator-associated arginine methyltransferase 1; CBP, CREB binding protein; CDC25A, cell division cycle 25A; CDK2, cyclin-dependent kinase 2; CDK4, cyclin-dependent kinase 4; CDK6, cyclin-dependent kinase 6; C-Myc, avian myelocytomatosis viral oncogene homolog; Cul2, cullin 2; DeMe, demethylation; DNMT1, DNA (cytosine-5-)-methyltransferase 1; DP1, transcription factor DP-1, TFDP1; E2F1, E2F transcription factor 1; DREAM, dimerization partner, RB-like, E2F and multi-vulval class B; E2F4, E2F transcription factor 4; E2F6, E2F transcription factor 6; E6AP, E6-associated protein, ubiquitin protein ligase E3A, UBE3A; E-Cadherin, epithelial cadherin; EGFR, epidermal growth factor receptor; EMT, epithelial mesenchymal transition; ERK1/2, mitogen-activated protein kinase 1/2; ET-1, endothelin 1; ETAR, endothelin A receptor; F-actin, filamentous actin; FOXM1, forkhead box M1; HCF-1, host cell factor 1; HLA-E, HLA class I histocompatibility antigen, alpha chain E; KDM6A, lysine demethylase 6A; KDM6B, lysine demethylase 6B; LIN54, protein lin-54 homolog; Me, methylation; MuvB, MuvB complex of five proteins including LIN9, LIN37, LIN52, RBBP4 and LIN54; NHERF-1, Na+/H+ exchanger regulatory factor; NK, natural killer; O-GlcNAc, O-Linked β-N-acetylglucosamine; OGT, protein O-GlcNAc transferase; p16, p16^INK4A, p14^ARF, cyclin dependent kinase inhibitor 2A, CDKN2A; p21, p21^WAF1/CIP1, cyclin-dependent kinase inhibitor 1A, CDKN1A; p27, p27^KIP1, cyclin dependent kinase inhibitor 1B, CDKN1B; p53, tumor protein p53, TP53; p300, E1A binding protein p300; P-Cadherin, placental cadherin; PI3K, phosphoinositide 3-kinase; pRb, phosphorylated retinoblastoma transcriptional corepressor 1; PRMT1, protein arginine N-methyltransferase 1; Raf, Raf proto-oncogene, serine/threonine kinase; Ras, RAS proto-oncogene, GTPase; STAT3, signal transducers and activators of transcription 3; Ub, ubiquitination.

Figure 5

Schematic view of anti-cancer mechanism of radiolabeled mAbs. Since many non-viable and necrotic cells with permeable membranes are present in tumors, allowing mAbs to access to interact with the intracellular antigens. In addition, intracellular antigens E6 and E7 can be released from cancer cells via necrosis and cell turnover. E6 or E7 specific mAbs bind to extracellular E6 and E7 and deliver cytotoxic radiation to this area. Surviving tumor cells including weak or no E6 or E7 expression were killed by radiation by the “cross-fire” effect produced by radiation in 360° spheres.

Figure 6

Schematic view of single‐chain variable fragment (scFv) antibody and nanobody. V_H, heavy chain variable domain; V_L, light chain variable domain; C_H, heavy chain constant domain; C_L, light chain constant domain; V_HH, single-domain antibody.