|Year : 2021 | Volume
| Issue : 2 | Page : 108-114
HPV and cervical cancer: An immunological aspect
Sanjay Singh1, Sukanya Tripathy2, Mohit Kumar Rai2, Durga Prasanna Misra2, Vikas Agarwal2
1 Department of Biotechnology, BBA University, Lucknow, India
2 Department of Clinical Immunology, SGPGIMS, Lucknow, India
|Date of Submission||31-May-2021|
|Date of Acceptance||26-Aug-2021|
|Date of Web Publication||23-Feb-2022|
Dr. Vikas Agarwal
Department of Clinical Immunology, SGPGIMS, Lucknow
Source of Support: None, Conflict of Interest: None
Evidence supports that the occurrence of cervical cancer is mainly due to viral infection and the most common virus found in association with this type of cancer is the Human papillomavirus (HPV), a DNA virus. The reason for virulence is its integration in the host’s genome and continual activity of E6 and E7 proteins, which further interfere with the tumor suppressor protein’s activity. The International Agency for Research on Cancer has classified 12 HPV types as group 1 carcinogens that have a high risk of carcinogenicity. Due to lack of access and utilization of preventative health care, the occurrence and death rates from cervical cancer remain considerable. The diagnosis of cervical cancer can be done through cytological screening programs and microbial screening. Knowing the microenvironment for the development of such a type of cancer plays a prominent role in the identification of preventive measures. Prevention of this type of cancer can be done through diagnosis at an early phase, with primary prevention using vaccines and secondary prevention using a highly sensitive HPV-DNA test and by propagating the knowledge of such infection and its cure. New biomarkers will be important to decide who among the HPV-positive women needs to be referred for further evaluation or treatment. The implementations of new prevention strategies is very important to completely eradicate such cancers. In this review, the microenvironment, etiology, and epidemiology of cervical cancer have been emphasized.
Keywords: E6 protein, E7 protein, epidemiology, human papillomavirus (HPV), immune response, treatment of HPV
|How to cite this article:|
Singh S, Tripathy S, Rai MK, Misra DP, Agarwal V. HPV and cervical cancer: An immunological aspect. J Curr Oncol 2021;4:108-14
| Introduction|| |
Human papillomavirus (HPV) is the most vernacular case of sexually transmitted disease in both males and females throughout the world, and a varied number of cases are present in developing countries. The Papillomaviruses are ubiquitous in nature and are found in varied humans as well as animals. These viruses show host specificity and more than 200 types of them have been recognized till date by analyzing DNA sequence. They infect mostly the epithelial cells and cause a variety of lesions such as warts, cervical neoplasia, and cancer. On the basis of their precursor lesions, HPVs are grouped into two categories: low-risk HPV and high-risk HPV. The types of low-risk HPV include 6, 11, 42, 43, and 44 whereas high-risk HPV involves 16, 18, 31, 33, 34, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, and 70. HPV is associated with many clinical manifestations, ranging from lesions to cancer. In most of the cases, it causes benign infection.
Cervical cancer globally affects nearly 500,000 women each year, among whom approximately 80% are found in developing countries. It arises in individuals who fail to resolve the infection and retain oncogene expression for years or decades. The regular gynecological screening and safe treatment of initial cancerous lesions have shown to be very effective in precluding squamous cervical cancer. The connection between genital HPV infections and cervical cancer was demonstrated for the first time by Harold zur Hausen, a German virologist in the early 1980s. zur Hausen was presented the Nobel Prize in Medicine or Physiology in 2008 for the worthy contribution in the field of science. Since then, exhaustive studies have been conducted and have aimed at finding the link between HPV and cervical squamous cell carcinoma. HPV-DNA is found in almost all cervical cancers (>99.7%), with HPV-16 being the most prevalent. Most cervical cancers initiate within the cervical transformation zone, which is a junction for the squamous or columnar epithelium.
Cervical cancer remains the fourth common cancer among women after breast cancer (2·1 million cases), colorectal cancer (0·8 million), and lung cancer (0·7 million). Incidence rates of this cancer, which are estimated at 13 per 100,000 women worldwide, vary widely depending on the country. Cervical cancer is the common cause of cancer-related deaths among women in eastern, western, middle, and southern Africa and Asia.
The present review deals with the worldwide epidemiology focusing on the Indian scenario, basic virology, etiogenesis of the disease, immunological perspective, and present vaccines for the disease.
| Cervical Cancer: Epidemiology|| |
Invasive cervical cancer (ICC) is a significant cause of cancer that is related to morbidity and mortality among women worldwide, with a very low geographic variability. Developed countries have attained considerable success in reducing the burden of incidence over the past six decades, and with annual incidence rates between 4 and 14 per 100,000. The low incidence is achieved through substantial health-care investments for screening programs and diagnostic workup in industrialized countries. In developing countries, cervical cancer is the leading cancer among women due to resource constraints and lack of good diagnostics; due to this, mortality rates are about five to six times higher in these countries. Rates are the highest in sub-Saharan Africa, South-Central Asia, and parts of South America, where ICC represents from a sixth up to a fifth of all cancers among women.
Cervical cancer is the most frequent cancer among women in India. India has a population of approximately 365.71 million women who are older than 15 years of age, and who are at a risk of developing cervical cancer. The current estimates indicate approximately 132,000 new cases diagnosed and 74,000 deaths annually in India, accounting to nearly one-third of the global cervical cancer deaths. Unlike other types of cancers, cervical cancer initiates early and peaks during the productive period of a woman’s life. The average age of rise in incidence is during 30–34 years and peaks at 55–65 years, with an average age of 40 years (age 21–67 years). Estimates suggest that more than 80% of the sexually active women acquire genital HPV by 50 years of age. At any given time, about 6.6% of women in the general population are estimated to harbor cervical HPV infection. HPV serotypes 16 and 18 account for nearly 76.7% of cervical cancer in India.
| Structure of Virus|| |
Papilloma virus belongs to the Papovaviridae family, among which HPV is a double-stranded DNA, nonenveloped capsid virus. Its structure possesses 7900 base pairs and it is arranged in a circle, which includes the codes for two key proteins known as L1 and L2. Infectivity proteins are expected to self-assemble from these two proteins, and act as the “immunogenes.” The virus is carried between humans through halts within the epidermis of the skin. Replication of the virus occurs within the squamous keratinocyte where it replicates, proliferates, and increases its virulence. The HPV enters, invades, and begins the process of replication within the squamous epithelial cells. Carcinogenicity of these HPV types for the cervix is due to the expression of two early genes, the E6 and E7 oncogenes. During this establishment of carcinogenicity, the HPV genome integrates into the epithelial cell genome and some of its genomic parts can be lost.
The International Agency for Research on Cancer has classified 12 HPV types. These 12 HPV belong to four species in a single evolutionary branch of the alpha genus, and all can infect the cervix. The other groups of possible carcinogens and rare carcinogens belong to the same branch of evolutionary history and are classified as group 2Aand 2B, respectively. HPV16 also causes most cancers that are linked to HPV in other anogenital epithelia and with oral cancer as well. HPV18 is second in terms of etiologic importance but it plays a more important role in adenocarcinomas [Figure 1].
|Figure 1: Structure of HPV depicting all the essential capsid proteins expressed on the viral surface|
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Recent findings suggest that the capsid of HPV is randomly arranged into a T = 7 icosahedral particle, with 72 L1 pentameric capsomeres linked via disulfide bonds between Cys175 and Cys428. A capsomere-hybrid virus-like particle (chVLP) was designed to incorporate multiple types of L1 pentamers by the reverse organization of single C175A and C428A L1 mutants, either of which alone constrains L1 pentamer particle self-assembly. This suggested that the co-assembly across nine HPV genotypes occurs at a defined equal molar stoichiometry, a part of the type or number of L1 sequences.
| Aetiogenesis of Cervical Cancer|| |
Usually, the viral life cycle is tightly regulated and is a well-coordinated process. During infection, the DNA randomly gets incorporated into the genome of the host, causing oncogenesis. Due to host evasion, the natural replication capacity of the virus diminishes and only two major viral oncogenes remain expressed, that is, E6 and E7. These proteins cause immortality in cells, further leading to cellular transformation and resulting in cancer development., This upregulation was observed in many studies interfering at the protein levels or RNA, which causes cell growth arrest and/or apoptosis.,,,,, It was found that E6 hinders cell survival pathways whereas E7 promotes cellular proliferation.,, Thus, these proteins are considered potent therapeutic targets for treatment and knowledge of their molecular mechanism is the key for therapy.
Molecular mechanism of E6
The E6 protein of HPV is 150 amino acids long, having two zinc fingers made by motifs CXXC., The cellular target of E6 is the tumor suppressor protein p53. The absence of HPV regulates p53 by the RING finger domain-containing ubiquitin ligase Mdm2. The HPV-positive cells express p53 turnover, which is regulated by HPV E6. An interaction of E6 with p300/CBP co-activators via the p53-dependent gene has been also found., p300 inhibits p53-dependent chromatin transcription, which causes activation of deacetylase enzyme, correlating with the inhibition of acetylation on p53 and nucleosomal core histones, altering p53 and p300 recruitment to chromatin [Figure 2].
|Figure 2: Schematic representation of E6 protein and its role in cellular proliferation of tumor cell progression|
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Molecular mechanism of E7
HPV E7 is 98 amino acid proteins long, having a C-terminal zinc-binding domain that is required for maintaining structural integrity., There are three conserved domains of protein, that is, CD1, CD2, and CD3. Their distinct function is provided in [Table 1]. The CD2 region of E7 contains the phosphorylation site of CKII and the LXCXE binding motif required for the binding of the retinoblastoma tumor suppressor (pRb) protein. The phosphate acceptor site of CKII is crucial for the transformation of E7 and its ability to provide progression in the S phase., Earlier studies have shown the chief role of pRb in regulation of the cell cycle. It controls the transition of the cell from G1 to the S phase. In cancerous cells, the pRb is phosphorylated in early G1 and is thus unable to interact with the E2F transcriptional factors and thus act as a transcriptional activator of promoters containing E2F sites. In the HPV-positive cell, LXCXE motif of E7 is targeted toward unphosphorylated pRb for degradation via the ubiquitin proteasome pathway. Inhibition of the pRb-E2F complex releases free E2F, leading to E2F-induced transcription and increased expression of cyclins A and E and CDK2. These processes are considered as detrimental for the progression of the cell cycle in dividing the epithelium, facilitating the replication of DNA [Figure 3].
|Figure 3: The figure represents the role of pRb and E2F in cell cycle and its alteration with E7 protein in cervical cancer|
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| Immunological Perspective of Cervical Cancer|| |
The immune system can reduce HPV infections up to a large extent, as it has been found that proliferative HPV16 E2- and E6-specific T-cell memory responses are significantly increased in HPV-negative women before infection. These types of responses are concurrent with the increased IFNγ and IL-5 production and reduced levels of IL-10.
The mechanism of progression is attributed to the infiltrative ability of T cells in cervical neoplastic tissues and metastatic lymph nodes. These infiltrating T cells show a wide range of distribution and are not specific for preferential regions within the E6 and E7 proteins. This might be specific for HPV-induced tumors, but it needs to be further investigated [Figure 4]. Within a single patient, the HPV-specific T-cell response is broad as is indicated by the recognition of multiple E6 and E7 epitopes and multiple T-cell receptor Vβ usage.
|Figure 4: Represents the immunological perspective of HPV. Innate and adaptive immune responses to HPV infection are moved away from effective TH1-like responses in genital verrucas and respiratory papillomas, causing HPV-induced disease. The adaptive immune response is polarized due to the failure of LCs to mature and then present peptides to T cells, which results in altered LC signaling that leads to a TH2 T-cell bias, when combined with the lack of NK activity|
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Natural killer (NK) cells play only a limited role in the immune surveillance of the primary tumor in patients with cervical cancer, as only low numbers of CD57 + CD3- cells, encompassing a subpopulation of NK cells, are infiltrating tumor tissue. Despite their absence at the tumor site, they are present in vast numbers in the peripheral blood and in the lymph system, where they may kill metastasizing cells.
Innate immunity in HPV
The innate immunity forms the nonspecific part of the immune system that is performed by the epithelial barrier, the complement system, and various cells that phagocytose antigens and present it to other cells or destroy them. The immune surveillance of the squamous epithelium of the cervix is performed by Langerhans cells (LCs), immature dendritic cells. The LCs are present in large amounts in the skin and mucosa, are thought to receive and process antigens so as to present them to the B and T cells, presenting both innate and adaptive immunity against the virus. Dendritic cells are considered to show special patterns on the pathogens using their Toll-like receptors and major histocompatibility complex to present the antigens to the T cells, and many times they are helped by inflammatory agents such as chemokines and cytokines. The LCs are unable to produce a successful immune response, which later becomes a part of viral tolerance tactics. Thus, it may be suggested that potential vaccines should be avoided using LC as a presenting agent without using co-stimuli. They are found on a variety of cells of innate immunity and are able to recognize endogenous and exogenous threats, particularly pathogen-associated molecular patterns and damage-associated molecular patterns. The upregulation of TLRs produces a proinflammatory expression profile that activates innate immunity. The double-stranded HPV-DNA is recognized primarily by TLR 9, and a series of interferons (INF-α, INF-β, and INF-ɣ) that is started. These pathways are marked by HPV oncoproteins showing an aberrant expression pattern that causes the virus tenacity and carcinogenic potential. The oncogenic E6 and E7 genes in HPV are found to be responsible for the decreased expression of TLR9, and they respond to DNA threats and evoke an innate immune reply. Later, it was found that an enhanced TLR 3 expression usually recognizes RNA viruses and is found in the dysplastic epithelium. In addition, INF- κ and IL10 causes a major hindrance in the premalignant or malignant epithelium. INF-κ reduced expression is found to have originated from either the addition of the methyl group to the INF-κ promoter or the direct decrease by the HPV oncogenes., Certain proteins such as monocyte chemotactic protein-1 and macrophage inflammatory protein aid in the accumulation of macrophages. These proteins appear to be downregulated directly or indirectly by HPV., Another major part of the innate immune response against viral attack is due to NK cells. It was observed that in HSILs and cervical cancer by HPV16, the NK-activating receptors NKp30 and NKp45 are considerably decreased, affecting the cytolytic functionality.
Adaptive immunity in HPV
Adaptive immunity is the particular immune response developed against the pathogens, which comprises B cells and T cells. B cells generate humoral immune response whereas T cells are divided into helper T cells, cytotoxic T cells, and regulatory T cells (Tregs) that perform a variety of functions. T-helper cells express the specific cell surface marker CD4 protein on their surface, setting the cytokine milieu, leading to the development of immune response. It was studied that IFN-ɣ and IL12 are used for the differentiation of Th0 to Th1, which elicits IFN- ɣ, lymphotoxin α, and IL2 (and IL10, TNF-α), which causes the activation of cell-mediated immunity. The balance between Th1 and Th2 must be kept invariable in order to sustain intracellular or extracellular attacks. In HPV lesions, both Th1 and Th2 phenotypes are suppressed due to the activity of the Treg cells.
| Vaccines and Treatment|| |
HPV transmission is influenced by sexual activity and age. The vast majority of the infections resolve spontaneously, and only a minority (<1%) of the HPV infections progress to cancer. The lifetime risk for genital HPV is 50%–80% and that of genital warts is approximately 5%. In women who undergo routine screening, the risk of having an abnormal Papanicolaou (Pap) smear is 35%, CIN is 20%, and ICC is <1% approximately. In women without routine screening, the risk for cervical cancer is up to 4%. The Pap test is used to find cellular abnormalities in cervical tissue, and to help in early diagnosis. HPV has become a necessary cause of cervical cancer due to its easy penetration into epithelial tissues.
With the advent of science and technology, many different treatment options are developed for the treatment of cervical cancer. The three basic treatments provided are: radiotherapy, surgery, and vaccines.
- a) Surgery: It is performed during earlier stages when the disease is diagnosed. This type of treatment comprises transvaginal hysterectomy and then removal of the uterus from the transabdominal region. It is based on the understanding that metastasis of cervical cancer occurs in nearer lymph nodes and the primary lesion reaches only nearby structures without clear clinical symptoms and signs, thus proving that the surgical removal is inefficient. Therefore, combinatorial treatment of surgery and radiotherapy is used in the treatment of patients.
- b) Radiotherapy: Among radiology centers around the world, the most effective way to treat cervical cancer is with a combined therapy that combines all the chemotherapy and radiation. Intracavitary brachytherapy and teleradiotherapy are combined. The first method involves destroying the malignant tissue on the cervix itself and its immediate surroundings, whereas other methods involve destroying secondary deposits in the area of the parametrium, regional and juxtaregional lymph nodes, and other organs of the small pelvis. This treatment has its own medical mechanism.
- c) Vaccines:: Vaccines are required for the prevention and not for the treatment of ICC. Although the vaccine conceives the VLPs as antigens to induce a potent immune response, if a vaccinated person is exposed then the person’s antibodies against the L1 protein will bind the virus and forbid it from releasing its genetic material. Two vaccines are used globally: a quadrivalent vaccine (Gardasil marketed by Merck) and a bivalent vaccine (Cervarix marketed by Glaxo Smith Kline). These vaccines are made by recombinant DNA technology producing noninfectious VLPs comprising the HPV L1 protein. Based on clinical trials, both vaccines are effective against CIN-2/3 and adenocarcinoma in situ (AIS) caused by HPV strains being the primary end point. Gardasil is a categorization of L1 proteins of HPV serotypes 16, 18, 6, and 11 with an aluminum-containing adjuvant. The respective three doses at 0, 2, and 6 months in more than 16,000 women aged 16–26 years from five different continents, including Asia, have shown absolute efficacy at a median follow-up of 1.9 years against types 16/18-related CIN-2/3 in the per-protocol analysis. This vaccine bestows security against both cervical cancer and genital warts.
Cervarix comprises L1 proteins of HPV serotypes 16 and 18 with AS04 as an adjuvant. Clinical trials with three doses of this vaccine at 0, 1, and 6 months in women globally has shown efficacy of 90% against type 16/18-related CIN-2/3 and AIS at the 15-month follow-up in the modified intention-to-treat analysis. Further follow-up studies in a subset of participants older than 4–5 years presented no evidence of declining immunity. The vaccine, unlike Gardasil, confers protection only against cervical cancer. Vaccinations aim at protecting the invasion of cervical cancer in other tissues.
| Conclusion|| |
The occurrence of cervical cancer is reduced in developed countries but still remains a significant problem in lesser developed countries. Challenges remain to keep this hazardous disease in check in such a way so that its cure can reach all socioeconomic classes. The early diagnostic technique and permanent cure of such a cancer is an important research focus. A more explorative study of the morphology of HPV is required for its appropriate and early cure. Also, there is an urgent need to conduct epidemiological studies in countries on the long-term efficacy, logistics, and economics of universal HPV vaccination in eligible females.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]