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

^* To whom correspondence should be addressed. E-mail: j.schultze{at}uni-bonn.de.

	Abstract

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]

Key Words: peptide vaccination, division arrest anergy, CTL