The goal of this work is to study mechanisms of homing that provide immune surveillance and homeostasis in the genital mucosa. The studies are based on a series of investigator-initiated clinical protocols which are funded by the NIH, testing therapeutic vaccines for the treatment of women with high grade cervical dysplasia (CIN2/3), the lesion which is the immediate precursor to invasive cervical cancer. CIN2/3 is a disease which should be susceptible to an HPV-specific T cell response. The antigenic targets, HPV16 E6 and E7, are non- 'self', and functionally required for disease initiation and persistence. CIN2/3 lesions are relatively accessible, and some of them do regress. The specific hypothesis behind this proposal is that CIN2/3 lesions mitigate the ability of localized immune effector cells to eliminate disease, and that the lesion microenvironment can be manipulated to enable immune-based therapeutic success. This work will analyze clinical specimens from a series of investigator-initiated trials, using therapeutic reagents developed by colleagues at our institution, and manufactured by NCI RAID (pNGVL4a-sig/E7 /HSP70), and as a kind gift from CelticPharma (TA-HPV). The long term goals of this work are to identify mechanisms of immune escape which contribute to the failure of HPV-specific adaptive responses to eradicate CIN2/3, to identify biomarkers predictive of response to immune-based therapies, and to develop combinatorial interventions to uncouple immune escape mechanisms. Specifically, we will: SA1: Determine the homing receptor profile on cervical T cells and expression of corresponding ligands in normal and CIN2/3 mucosa. The characterization of homing mechanisms for cervical mucosa will allow monitoring of immune responses that are likely to traffic to the genital tract, may suggest efficient routes of immunization, e.g., oral or nasal or genital priming, and in cases in which we can determine specificity, may also allow us to estimate the extent to which detectable systemic immune responses correlate with measures in the lesion site. SA2: Determine the immunologic signature of persistent CIN2/3: We will determine the phenotype, functional potential, distribution and co localization of resident immune cell populations in normal cervical mucosa and in CIN2/3, determine the chemokine/chemokine receptor profile associated with presence or absence of CD8+ infiltration in mucosal epithelial and stromal compartments, and determine the chemokine profile at T0 of subjects who respond to vaccination, and of subjects who respond to imiquimod, compared to those who do not.
Mechanisms of mucosal immune evasion in high grade cervical dysplasia The identification of homing mechanisms for genital immune responses in HPV-associated disease is likely to suggest optimal routes of vaccination, to inform monitoring of immune responses likely to traffic to the genital mucosa, and to determine the extent to which immune responses in the cervix can be detected or correlated with measurements in the peripheral blood. From the standpoint of development of T cell therapies for malignancies, because dysplastic cervical lesions are relatively accessible, and mechanisms of lesion- mediated immune suppression common to many human solid tumors are likely to distinguish responders from non-responders, these studies present an opportunity to test proof-of-principle of immune therapeutic combinations.
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