Success or failure of vaccination for HPV16-positive vulvar lesions correlates with kinetics and phenotype of induced T-cell responses

Abstract

One half of a group of 20 patients with human papillomavirus type 16 (HPV16)-induced vulvar intraepithelial neoplasia grade 3 displayed a complete regression (CR) after therapeutic vaccination with HPV16 E6/E7 synthetic long peptides. Patients with relatively larger lesions generally did not display a CR. To investigate immune correlates of treatment failure, patients were grouped according to median lesion size at study entry, and HPV16-specific immunity was analyzed at different time points by complementary immunological assays. The group of patients with smaller lesions displayed stronger and broader vaccine-prompted HPV16-specific proliferative responses with higher IFNγ (P = 0.0003) and IL-5 (P < 0.0001) levels than patients with large lesions. Characteristically, this response was accompanied by a distinct peak in cytokine levels after the first vaccination. In contrast, the patient group with larger lesions mounted higher frequencies of HPV16-specific CD4 + CD25 + Foxp3 + T cells (P = 0.005) and displayed a lower HPV16-specific IFNγ/IL-10 ratio after vaccination (P < 0.01). No disparity in T memory immunity to control antigens was found, indicating that the differences in HPV-specific immunity did not reflect general immune failure. We observed a strong correlation between a defined set of vaccine-prompted specific immune responses and the clinical efficacy of therapeutic vaccination. Notably, a high ratio of HPV16-specific vaccine-prompted effector T cells to HPV16-specific CD4 + CD25 + Foxp3 + T cells was predictive of clinical success. Foxp3 + T cells have been associated previously with impaired immunity in malignancies. Here we demonstrate that the vaccine-prompted level of this population is associated with early treatment failure.human papilloma virus | immunomonitoring | therapeutic vaccine | regulatory T cells

Systemic and local human papillomavirus 16‐specific T‐cell immunity in patients with head and neck cancer

“…In HNSCC the ratio between CD8þ and regulatory T cells is associated with disease. 5,33 Similarly, in HPV16 induced genital malignancies the presence of FoxP3 positive as well as FoxP3 negative HPV16 specific regulatory T cells in tumor and LN is described 30,36,38 and a low CD8/Treg T-cell ratio is associated with worse outcome. 39 While the regulatory function of the CD4þCD25þFoxp3þ T cells present in TILs needs to be confirmed, at least one of our isolated clones clearly exerted regulatory function.…”

“…In TIL we find different subsets of HPV16-specific T cells (Th1, Th2, CTL and Tregs) with different cytokine profiles (IL-2, IFNc, IL-5) comparable to what is found in anogenital HPV16 induced lesions. 29,35,36 Together this advocates that local adaptive immune cells might play a role in the response to therapy and the altered survival of this patient group.…”

Tumor-Infiltrating Regulatory T Cells: Phenotype, Role, Mechanism of Expansion In Situ and Clinical Significance

“…In human, the group of Peter Van der Bruggen has demonstrated that the CD4 + T-cell response of melanoma patients to a MAGE-A3-derived peptide vaccine involves regulatory T cells [88]. In individuals vaccinated with E6/E7-derived long peptides, immunosuppressive cells has been shown to expand [89], correlating to the development of resistance against an anti-HPV therapeutic vaccine [90]. A better identification of the specificity of Tregs in cancer patients will help to design TAAbased vaccine that induce optimal Teff responses while failing to activate Tregs to significant extents.…”

Harnessing the immune response to treat cancer

“…The importance of a robust effector T-cell response in mediating successful outcomes to immunotherapy has been recently shown in a clinical human papillomavirus vaccine trial for pre-malignant vulval intraepithelial neoplasia, in which measured T-cell responses strongly correlated with regression of lesions (Kenter et al, 2009;Welters et al, 2010; Figure 2). However, in other clinical trials of tumour vaccines against larger, invasive malignancies the effective generation of tumour antigenspecific T cells in peripheral blood has not predicted clinical efficacy Gajewski et al, 2006).…”