Cervical mucosal CD8 T cells are more predictive of HPV lesion regression than systemic HPV-specific response (48.13)

Abstract Virtually all squamous cervical cancers and their dysplastic precursor lesions (CIN2/3), are caused by infection with human papillomavirus (HPV), most commonly, HPV16. Although 20-25% of HPV16+ CIN2/3 undergo complete regression, HPV16-specific T cell immunity in blood is only marginally detectable, and does not correlate with lesion regression. To better understand immunity within the cervical microenvironment, we studied T cells and the expression of vascular adhesion receptors in normal and dysplastic human cervical mucosa. The majority of CIN2/3 CD8+ T cells had an activated memory phenotype, and nearly all expressed α4β7. Regression was predicted by lesional intraepithelial CD8 T cells, whereas in persistent disease, CD8 T cells were restricted to the lesional subepithelial stroma. Expression of VCAM-1 and MAdCAM-1, two ligands that support the entry of α4β7+ T cells into tissues, correlated with CD8 infiltrates. Our data provide evidence that reduced adhesion receptor expression on CIN2/3 vasculature may restrict the entry of CD8 T cells into dysplastic mucosa, thereby preventing immunologic clearance. Immune therapies for cervical dysplasia should generate CD8 T cells that express α4β7, and include local manipulation to induce vascular expression of adhesion receptors that can support the entry of these cells into lesional epithelium.