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Cancer Vaccine Enhanced, Non–Tumor-Reactive CD8⁺ T Cells Exhibit a Distinct Molecular Program Associated with "Division Arrest Anergy"

Life and Medical Sciences Bonn, Laboratories for ¹ Genomics and Immunoregulation and ² Chemical Biology, University of Bonn, Bonn, Germany; ³ Molecular Tumor Biology and Tumor Immunology, University of Cologne, Cologne, Germany; and ⁴ Medizinische Klinik II, Hämatologie-Onkologie, Krankenhaus Nordwest, Frankfurt, Germany

Requests for reprints: Joachim L. Schultze, Life and Medical Sciences Bonn, Laboratory for Genomics and Immunoregulation, University of Bonn, Karlrobert-Kreiten-Str. 13, D-53115 Bonn, Germany. Phone: 49-228-73-60102; Fax: 49-228-73-5499; E-mail: j.schultze{at}uni-bonn.de.

Key Words: peptide vaccination • division arrest anergy • CTL

Immune-mediated tumor rejection relies on fully functional T-cell responses and neutralization of an adverse tumor microenvironment. In clinical trials, we detected peptide-specific but non–tumor-reactive and therefore not fully functional CD8⁺ T cells post-vaccination against tumor antigens. Understanding the molecular mechanisms behind nontumor reactivity will be a prerequisite to overcome this CD8⁺ T-cell deviation. We report that these non–tumor-reactive CD8⁺ T cells are characterized by a molecular program associated with hallmarks of "division arrest anergy." Non–tumor-reactive CD8⁺ T cells are characterized by coexpression of CD7, CD25, and CD69 as well as elevated levels of lck^p505 and p27^kip1. In vivo quantification revealed high prevalence of non–tumor-reactive CD8⁺ T cells with increased levels during cancer vaccination. Furthermore, their presence was associated with a trend toward shorter survival. Dynamics and frequencies of non–target-reactive CD8⁺ T cells need to be further addressed in context of therapeutic vaccine development in cancer, chronic infections, and autoimmune diseases. [Cancer Res 2009;69(10):4346–54]