Persistent cervical mucosal infection with oncogenic strains of human papillomavirus (HPV), most commonly type 16, is the cause of virtually all squamous cancers of the cervix (1
). Current screening strategies to identify preinvasive disease, using pap smears, detection of oncogenic HPV genotypes, or even direct visual inspection, require repeated visits to health care providers as well as the existence of laboratory infrastructure. Although on balance, screening is indeed cost-effective, it is costly. In the United States, annual direct costs associated with HPV-related conditions among insured women have been estimated at $2.25–4.6 billion (2005 United States dollars), which include costs of routine screening, evaluation of false-positive Papanicolau tests, evaluation and care of preinvasive disease, and the care of women with invasive cancer (3
). Recently available prophylactic vaccines for HPV16, -18, -6, and -11 (Gardasil, Merck, Whitehouse Station, NJ) or HPV16 and -18 (Cervarix, GlaxoSmithKline, Research Triangle Park, NC) are expensive, involve three sequential vaccinations in a 6-mo time frame, and also require intense infrastructure for delivery. In the United States, uptake of prophylactic HPV vaccines in eligible cohorts is low; the Centers for Disease Control reported that in 2009, only 26.7% of eligible girls (age 13–17 y) had completed the three-vaccination series. Among women who initiated vaccination, a substantial proportion (44.3%) did not complete the three-vaccination regimen. Among adolescents below the poverty level, half (51.9%) of those who initiated vaccination failed to complete the series (7
). Altogether, because screening and prevention are cumbersome and expensive, cervical cancer remains the second leading cause of cancer death in women worldwide (8
). Even in a high-resource setting such as the United States, the burden of disease is not likely to change in our lifetime (9
High-grade cervical intraepithelial neoplasia (CIN2/3), the dysplastic intraepithelial precursor to invasive disease, is a lesion that should be susceptible to an HPV-specific immune response. The development of cervical cancer and its precursor CIN lesions are associated with integration of the HPV genome into the host genome, with subsequent expression of two HPV gene products, E6 and E7, which inactivate p53 and pRb, respectively. Expression of these viral, nonself proteins is functionally required to initiate and maintain the transformed phenotype, thereby providing true tumor-associated antigenic targets (10
Whereas all cervical squamous carcinomas arise from untreated CIN2/3, not all CIN2/3 lesions progress to invasive cancer. We and others (12
) have reported that across all HPV types, ~35% of CIN2/3 undergo regression in a time frame of 4–6 mo. Lesions associated with HPV16 are less likely to undergo regression than lesions associated with other HPV types; in this time frame, ~25% of HPV16-associated CIN2/3 undergo regression, which is presumably immunologically mediated (13
). However, in the peripheral blood of immune-competent subjects with HPV16+
CIN2/3, T cell responses to HPV16 E6 and E7 are only marginal, requiring ex vivo sensitization for detection, both in women whose lesions regress and in those whose lesions do not (15
). Neither the magnitude nor the breadth of naturally occurring responses in the blood are robust predictors of regression of preinvasive HPV disease of the cervix.
Immunologic data from a recent clinical trial testing therapeutic vaccination targeting HPV16 E6 and E7 in subjects with HPV16-associated vulvar intraepithelial neoplasia (VIN) highlight this conundrum (18
). Complete regression occurred postvaccination in 40% of subjects. This outcome is remarkable because clinically, preinvasive HPV-associated disease of the vulva is considerably more recalcitrant than cervical disease; untreated, virtually no VIN lesions undergo regression. However, in complete regressors in this study, the median IFN-γ immune response to HPV16 E6/E7 was in the neighborhood of 50 spot-forming units/105
PBMCs, after 4 d of ex vivo expansion. Moreover, the distribution of blood immune responses in nonegressors significantly overlapped with responses in regressors; in fact, some nonregressors had immune responses of greater breadth and magnitude than regressors.
The data in both unvaccinated and vaccinated subjects demonstrate that weak blood responses to viral Ags can nonetheless be associated with disease regression and raise the question of whether it is possible to identify immune responses in the target tissue that can predict either disease outcome or the likelihood of a clinical response to immune manipulation. In this paper, we present our findings that dysplastic epithelium excludes recruited Ag-experienced T cells, that cervical tissue T cells express the α4β7 surface integrin, and that lesional epithelial vascular expression of mucosal addressin cell adhesion molecule (MAdCAM) correlates directly with T cell infiltration. These data provide evidence that one mechanism that may permit preinvasive HPV lesions to elude immune-mediated clearance is by preventing egress of CD8 T cells into lesional epithelium. Furthermore, our data suggest that clinical trials testing immune-based therapies for HPV-associated disease should include, in addition to eliciting CD8+ T cell responses that are capable of homing to the cervical mucosa, local manipulation to activate lesion-associated vascular endothelium to enhance extravasation of effector cells to the lesional epithelial compartment.