Intramuscular Therapeutic Vaccination Targeting HPV16 Induces T Cell Responses That Localize in Mucosal Lesions

Abstract

About 25% of high-grade cervical intraepithelial neoplasias (CIN2/3) caused by human papillomavirus serotype 16 (HPV16) undergo complete spontaneous regression. However, to date, therapeutic vaccination strategies for HPV disease have yielded limited success when measured by their ability to induce robust peripheral blood T cell responses to vaccine antigen. We report marked immunologic changes in the target lesion microenvironment after intramuscular therapeutic vaccination targeting HPV16 E6/E7 antigens, in subjects with CIN2/3 who had modest detectable responses in circulating T lymphocytes. Histologic and molecular changes, including markedly (average threefold) increased intensity of CD8+ T cell infiltrates in both the stromal and epithelial compartments, suggest an effector response to vaccination. Postvaccination cervical tissue immune infiltrates included organized tertiary lymphoid-like structures in the stroma subjacent to residual intraepithelial lesions and, unlike infiltrates in unvaccinated lesions, showed evidence of proliferation induced by recognition of cognate antigen. At a molecular level, these histologic changes in the stroma were characterized by increased expression of genes associated with immune activation (CXCR3) and effector function (Tbet and IFNβ), and were also associated with an immunologic signature in the overlying dysplastic epithelium. High-throughput T cell receptor sequencing of unmanipulated specimens identified clonal expansions in the tissue that were not readily detectable in peripheral blood. Together, these findings indicate that peripheral therapeutic vaccination to HPV antigens can induce a robust tissue-localized effector immune response, and that analyses of immune responses at sites of antigen are likely to be much more informative than analyses of cells that remain in the circulation.

Self-adjuvanting nanoemulsion targeting dendritic cell receptor Clec9A enables antigen-specific immunotherapy

“…Indeed, HPV16 synthetic long peptides used within conventional vaccination approaches induced strong antitumor immunity and clinical responses in patients with HPV16-driven carcinomas (50)(51)(52). More recently, neoantigen vaccines in the form of RNA polyepitopes or based on the use of synthetic long peptides administered with adjuvant were shown to elicit robust specific T cell responses to advanced melanoma, with potential clinical benefits (53,54).…”

From mice to humans: developments in cancer immunoediting

“…Indeed, in melanoma, breast, lung, and colorectal carcinomas, high densities of TLSs have been reported to correlate with a favorable prognosis (36). Strikingly, TLSs are induced in cervical carcinomas (37) or pancreatic ductal cancer (38) upon vaccination with TSMAs. That TLSs are necessary for generating clinically efficient immune reactions is supported by the fact that a high density of CD8 + T cells is associated with longer patient survival when tumors display high TLS densities in lung (39), colorectal (40), and renal cell cancers (41).…”

Orchestration and Prognostic Significance of Immune Checkpoints in the Microenvironment of Primary and Metastatic Renal Cell Cancer

“…In the vast majority of cancers, tumor infiltration by CD8 þ memory cytotoxic T cells and Th1 cells is associated with good clinical outcome (1). In addition, it has been reported that an organized local immune reaction, characterized by the presence of mature dendritic cells (DC) localized in tumor-associated tertiary lymphoid structures (TLS), is necessary to orchestrate this cytotoxic and Th1 immune contexture and is associated with good clinical outcome (3)(4)(5)(6)(7)(8) and response to therapeutic vaccines (9,10). However, several recent findings challenge this concept of the unequivocal relation of effector memory CD8 þ T-cell infiltration with a good clinical outcome in cancer.…”