T-cell immunity against tumors, a delicate balancing act involving dendritic cells

Abstract

Abstract T-cell immunity occurs naturally against tumors induced by viruses and other causes. In the latter case self antigens are increasingly found to be targets of tumor associated CTL. In all categories of tumors the T cell response usually falls short of the maximally possible response. This situation calls for vaccination, primarily in situations of low tumor burden and adoptive transfer with tumor specific T cells in case of higher tumor burden. We recently observed that the outcome of immunization with vaccines containing tumor virus CTL epitopes strongly depends on mode of epitope delivery. Surprisingly, vaccination with MHC class I binding peptides cause CTL tolerance associated with enhanced tumor outgrowth rather than immunity. Such specific CTL tolerance can be induced by a single injection of 1 μg of peptide in adjuvant. However, in vivo presentation of the same peptides on dendritic cells or in viral vector (adenovirus) causes strong antitumor protection. Thus tumors may escape from immune attack by specific tolerance induction. Tumor specificity of autoreactive CTL can be achieved by T cells directed against tumor associated self antigens of limited tissue distribution. Alternatively useful CTL can be directed against strongly overexpressed self antigens, as illustrated in our lab by the successful eradication of tumors overexpressing wild type p53 tumor suppressor protein, by the adoptive transfer of a wild p53-specific CTL clone. Apparently the low expression of p53 in many tissues does not cause the CTL clone to inflict tissue damage, while the p53 overexpressing tumor cells are specifically targeted and eradicated. Recently we showed that CD40 signalling can replace CD4+ T-cells in priming of helper dependent tumor-specific CD8+ responses. Blockade of CD40L results in profound inhibition of CTL priming that is overcome by CD40 signalling. CD40 signalling converted CTL tolerization by a tolerogenic peptide into strong CTL priming. Moreover, supplementation of an already protective tumor-specific peptide vaccine with a CD40 activating antibody endows this vaccine with therapeutic CTL activity in tumor-bearing mice. The CD40–CD40L pair acts as a switch determining CTL priming or tolerance. This supports the clinical use of CD40 stimulating agents as components of anticancer vaccines.