Persistent antigen at vaccination sites induces tumor-specific CD8+ T cell sequestration, dysfunction and deletion

Abstract

Cancer vaccines have had limited success in eliminating tumors in patients. Here Willem Overwijk and colleagues report that one reason for the failure of peptide-based vaccines may be their formulation. Their research shows that peptides formulated in incomplete Freund's adjuvant sequester CD8+ T cells at the site of injection, leading to T cell dysfunction and eventual apoptosis. A peptide and adjuvant formulation that did not persist long term at the injection site showed superior ability to induce a functional antitumor T cell response. To understand why cancer vaccine–induced T cells often do not eradicate tumors, we studied immune responses in mice vaccinated with gp100 melanoma peptide in incomplete Freund's adjuvant (peptide/IFA), which is commonly used in clinical cancer vaccine trials. Peptide/IFA vaccination primed tumor-specific CD8+ T cells, which accumulated not in tumors but rather at the persisting, antigen-rich vaccination site. Once there, primed T cells became dysfunctional and underwent antigen-driven, interferon-γ (IFN-γ)- and Fas ligand (FasL)-mediated apoptosis, resulting in hyporesponsiveness to subsequent vaccination. Provision of CD40-specific antibody, Toll-like receptor 7 (TLR7) agonist and interleukin-2 (IL-2) reduced T cell apoptosis but did not prevent vaccination-site sequestration. A nonpersisting vaccine formulation shifted T cell localization toward tumors, inducing superior antitumor activity while reducing systemic T cell dysfunction and promoting memory formation. These data show that persisting vaccine depots can induce specific T cell sequestration, dysfunction and deletion at vaccination sites; short-lived formulations may overcome these limitations and result in greater therapeutic efficacy of peptide-based cancer vaccines.