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

T-cell immunity occurs naturally against tumors induced by viruses and othe r causes. In the latter case self antigens are increasingly found to be tar gets of tumor associated CTL. In all categories of tumors the T cell respon se usually falls short of the maximally possible response. This situation c alls for vaccination, primarily in situations of low tumor burden and adopt ive transfer with tumor specific T cells in case of higher tumor burden, We recently observed that the outcome of immunization with vaccines containin g tumor virus CTL epitopes strongly depends on mode of epitope delivery. Su rprisingly, vaccination with MHC class I binding peptides cause CTL toleran ce associated with enhanced tumor outgrowth rather than immunity. Such spec ific CTL tolerance can be induced by a single injection of 1 mug of peptide in adjuvant, However, in vivo presentation of the same peptides on dendrit ic 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. Alt ernatively useful CTL can be directed against strongly overexpressed self a ntigens, as illustrated in our lab by the successful eradication of tumors overexpressing wild type p53 tumor suppressor protein, by the adoptive tran sfer 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, whi le the p53 overexpressing tumor cells are specifically targeted and eradica ted. Recently we showed that CD40 signalling can replace CD4+ T-cells in pr iming of helper dependent tumor-specific CD8+ responses. Blockade of CD40L results in profound inhibition of CTL priming that is overcome by CD40 sign alling. CD40 signalling converted CTL tolerization by a tolerogenic peptide into strong CTL priming. Moreover. supplementation of an already protectiv e tumor-specific peptide vaccine with a CD40 activating antibody endows thi s vaccine with therapeutic CTL activity in tumor-bearing mice. The CD40-CD4 0L pair acts as a switch determining CTL priming or tolerance. This support s the clinical use of CD40 stimulating agents as components of anticancer v accines. (C) 2001 Editions scientifiques et medicales Elsevier SAS.