title: Persistent antigen at vaccination sites induces tumor-specific CD8⁺ T cell sequestration, dysfunction and deletion.
abstract: 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.
authors: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors: Yared
authors: Y
authors: Hailemichael
authors: Zhimin
authors: Z
authors: Dai
authors: Nina
authors: N
authors: Jaffarzad
authors: Yang
authors: Y
authors: Ye
authors: Miguel A
authors: MA
authors: Medina
authors: Xue-Fei
authors: XF
authors: Huang
authors: Stephanie M
authors: SM
authors: Dorta-Estremera
authors: Nathaniel R
authors: NR
authors: Greeley
authors: Giovanni
authors: G
authors: Nitti
authors: Weiyi
authors: W
authors: Peng
authors: Chengwen
authors: C
authors: Liu
authors: Yanyan
authors: Y
authors: Lou
authors: Zhiqiang
authors: Z
authors: Wang
authors: Wencai
authors: W
authors: Ma
authors: Brian
authors: B
authors: Rabinovich
authors: Ryan T
authors: RT
authors: Sowell
authors: Kimberly S
authors: KS
authors: Schluns
authors: Richard E
authors: RE
authors: Davis
authors: Patrick
authors: P
authors: Hwu
authors: Willem W
authors: WW
authors: Overwijk
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D017209:Apoptosis / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology / Q000494:pharmacology*; D053222:Fas Ligand Protein / Q000502:physiology; D005260:Female; D007371:Interferon-gamma / Q000502:physiology; D008546:Melanoma, Experimental / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D019496:Cancer Vaccines; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D007371:Interferon-gamma