Although unprecedented improvements in our ability to diagnose and treat cancer have driven a decline in incidence and mortality rates for most cancers in the United States, notable exceptions to this trend include oropharyngeal, anal, and vulvar cancers in patients who harbor the human papillomavirus (HPV).
While HPV is most famously the cause of cervical cancers, it is now known to be associated with a variety of other tumor types in which HPV-associated disease is on the rise. Cervical cancer provides proof that HPV-associated disease can be curbed by effective screening and preventive vaccination, but many patients still die despite these advances.
There is a pressing need to develop novel treatments to replace the use of highly invasive and morbid standard therapies. An improved understanding of the natural history of HPV, its interaction with the host immune system, and the distinct molecular alterations underlying HPV-positive cancers, are fueling development of new drugs, particularly immunotherapies geared toward generating an HPV-specific immune response (Table).
A Cancer-Causing Virus
Vaccine Strategies Against HPV-Infected Lesions
This figure illustrates elements of the tumor microenvironment that potentially could support immunebased therapies against HPV-associated cancers: the adaptive immune cells CD4, CD8, and Treg; innate immune cells such as dendritic cells (DC) and natural killer cells (NKT); and the regulatory cytokines IL-10, TGFβ, IFγ-. The goal would be to generate immune cells to prevent reinfection (inset).
Bergot AS, Kassianos A, Frazer IH, Mittal D. New approaches to immunotherapy for HPV associated cancers. Cancers (Basel). 2011;3(3):3461-3495.
In the mid-1970s, German virologist Harald zur Hausen first made the causative link between HPV and cervical cancer, a discovery that resulted in his receiving a Nobel Prize. HPVs are a large group of related viruses responsible for more than 170 different types of HPV that preferentially infect the mucosa of the genitals, upper respiratory tract, or skin.
It is alpha-HPVs, which infect the mucosal tissue and are most commonly spread through direct and indirect sexual contact, that have gained notoriety for their ability to cause cancer.
Proportion of Cancer Caused by HPV in the United States
HPV infection causes virtually all cases of cervical cancer and a substantial proportion of several other cancers.
Source: Schiller JT, Lowy DR. Understanding and learning from the sucess of prophylactic human papillomavirus vaccines. Nat Rev Microbiol. 2012;10(10):681-692.
Courtesy National Cancer Institute
These strains are categorized by their oncogenic potential as high-, intermediate- and low-risk, with HPV16 and HPV18 being most highly oncogenic. Up to 90% of sexually active individuals will be infected with at least one type of HPV at some point in their lives and around half of those cases will involve high-risk subtypes. Worldwide, the virus is responsible for around 5% of all human cancers.
Our understanding of precisely how HPV causes cancer is still evolving, and one of the most significant conundrums facing researchers is why not everyone infected with HPV develops cancer. The vast majority of patients may not even realize they are infected, since the virus is typically cleared by the immune system in less than 2 years. But when the virus persists for longer and the immune response fails, cancer arises.
HPV infects epithelial cells and hijacks the cellular machinery to generate viral proteins. The HPV genome is arranged into eight known genes: six early genes (E1, E2, E4, E5, E6, and E7) and two late genes (L1 and L2). (Figure)
. The proteins encoded by these genes promote viral replication and assembly by driving many of the hallmarks of cancer, such as excessive growth, promoting angiogenesis, and avoidance of apoptosis.
Figure. Genomic Structure of HPV-16
Courtesy National Cancer Institute
The E6 and E7 proteins are the most significant drivers of cancer and their bestcharacterized role in carcinogenesis involves suppression of the p53 and retinoblastoma protein (pRb) tumor suppressor pathways. Removal of the tumor suppressive activities of these proteins contributes to the genetic instability that is a central characteristic of cancer. Other mechanisms of HPV-induced oncogenesis are beginning to be uncovered, notably the integration of the HPV genome into the host genome and the ability of HPV to suppress the immune response.Curbing Cervical Cancer