HPV-associated neoplasia of the cervix presents a compelling opportunity to test antigen-specific immunotherapies because expression of two nonself, viral antigens, E6 and E7, are together functionally required to initiate and maintain high grade dysplastic lesions (CIN2/3), the lesion which is the immediate precursor to invasive cervical cancer. Expression of these proteins is functionally required to maintain the transformed phenotype.
Globally, HPV type 16 alone accounts for over half of all cervical malignancies. Weak but reproducibly measurable endogenous HPV-specific T cell responses in peripheral circulating lymphocytes (PBLs) obtained from CIN2/3 patients suggest that viral antigens are presented to and recognized by the immune system. In fact, between 20-25% of established CIN2/3 lesions regress completely over a 15-week prospective study window. However, the fact that neither the vigor nor the breadth of endogenous responses to HPV16 antigens measured in the peripheral blood appears to correlate consistently with lesion regression implies either that HPV16 E7-specific effector cells do not consistently access lesions, or that they do, and are dysfunctional in the lesion milieu.
The overall goal of this work is to determine whether we can measure molecular evidence of common mechanisms of immune suppression in CIN2/3 lesions. Two likely mechanisms of immunologic failure in the clinical setting of persistent viral infection of the lower genital tract mucosa include (1) expression of inhibitory ligands, both by lesional epithelial cells and by polarized antigen presenting cells (APCs) associated with lesions, and (2) recruitment and expansion of regulatory T cells (Treg) as a function of self-limiting immunologic homeostasis.
The overall hypothesis for this proposal is that lesion-mediated immune conditioning plays a central role in shaping the host immune response very early in cervical disease, well before invasion. We will determine whether the local immune microenvironment correlates with either the quality or the magnitude of endogenous immune response to HPV antigens. As a corollary, we will determine whether the quality of endogenous, baseline response to HPV antigens correlates with subsequent response to therapeutic vaccination. Finally, we will determine whether direct manipulation of the immunologic milieu to change an essentially tolerogenic setting enhances effector activity of vaccine-induced response.