Recent evidence has resurrected the concept of specialized populations of T lymphocytes that are able to suppress an antigenspecific immune response. T-regulatory cells (T-reg) have been characterized as CD4 þ CD25 þ T cells. Previous reports describing differential gene expression analysis have shown that the glucocorticoid-induced tumor necrosis family receptor family-related gene (GITR) is upregulated in these cells. Furthermore, antibodies specific for GITR have been shown to inhibit the T-suppressor function of CD4 þ CD25 þ T-reg. The ligands for both mouse and human GITR have been cloned recently. We have inserted the sequences for natural, membrane-bound GITR-ligand (GITR-L) and a truncated secreted form of GITR-L (GITR-Lsol) into the adenovirus-5 genome. Coculture experiments show that cells infected with Ad-GITR-L and supernatants from cells infected with Ad-GITR-Lsol can increase the proliferation of both CD4 þ CD25-and CD8 þ T cells in response to anti-CD3 stimulation, in the presence, as well as in the absence, of CD4 þ CD25 þ T cells. The virus constructs were injected into growing B16 melanoma tumors. Ad-GITR-L was shown to attract infiltration with both CD4 þ and CD8 þ T cells. Both constructs were shown to inhibit tumor growth.

A variety of adoptive cellular strategies, aimed at boosting the immune system, have been tested in the management of metastatic diseases. Despite the drawbacks associated with ex vivo cell manipulation and upscaling, several such approaches have been assessed in the clinic. The use of lymphokine-activated killer (LAK) cells, auto-lymphocyte therapy (ALT) and tumor-infiltrating lymphocytes (TIL) have been the best studied and further trials are ongoing. Thus far, these approaches have not consistently shown benefit when compared to standard immune-based treatment with biologic response modifiers, notably, high-dose interleukin-2 (IL-2). More recently, it has been shown, in various animal models, that the ex vivo transfer of genes to cells of the immune system can have a dramatic impact on cancer immunotherapy. The application of gene transfer techniques to immunotherapy has animated the field of cell-based cancer therapy research. A wide variety of viral and non-viral gene transfer methods have been investigated in this context. Ex vivo strategies include gene delivery into tumor cells and into cellular components of the immune system, including cytotoxic T cells, NK, macrophages and dendritic cells (DC). Several of these approaches have already been translated into cancer therapy clinical trials. In this review, we focus on the rationale and types of ex vivo gene-based immunotherapy of cancer. Finally, the use of genetically modified DC for tumor vaccination and its prospects are discussed.

Au cours de son dévelop-pement, la tumeur met en place des mécanismes d'échappement lui permettant de croître à l'insu du système immunitaire. Les cellules tumorales sous-expriment certaines de leur protéine de surface, impliquées dans la reconnaissance par le système immunitaire. Elles peuvent également réguler négativement la prolifération des lymphocytes T, notamment en favorisant la croissance d'une population de lymphocytes T régulateurs. Cette revue détaille certains des processus impliqués dans les mécanismes d'échap-pement tumoraux avant de se focaliser sur le développement et le rôle des lymphocytes T régulateurs.Abstract: During its growing, tumor develops evasion process against the host immune system. Tumor cells are able to down-regulate proteins expression on their surface, which are implicated in immune recognition. They down-regulate the proliferation of tumor-specific cytotoxic T cells by promoting regulatory T cells development. This review list some of the process involved in tumor escape and focus on regulatory T cells appearance and role.

Efforts to follow tumor-specific immune responses in patients are often thwarted by lack of knowledge of the appropriate tumor antigens and the CTL epitopes of those antigens. There is, therefore, a growing need for techniques to monitor tumor-specific immune responses in settings where tumor antigens, and antigenic epitopes, remain unidentified. Here we describe a novel system to follow tumor-specific CTL immune responses. A truncated, soluble murine class I MHC (H-2Db) molecule was fused with a rat IgG2a Fc, in order to allow secretion of the complex. Tumor-specific CTL could then be detected as a result of the complex fastening to specific T cell receptors (TCR). These constructs were inserted into the genome of a recombinant adenovirus vector. Infection of tumor cells with these adenovirus constructs results in the secretion of the complexes into the culture supernatant. These soluble divalent class I MHC molecules were used to detect and activate specific CTL populations.

Le développement d'une tumeur au sein d'un organisme est étroitement lié à son système immunitaire. Il est clairement établi qu'il existe un processus d'immunosurveillance qui protège l'hôte de la mise en place d'un foyer tumoral. Cependant, il est également admis que le système immunitaire facilite la progression tumorale, notamment en façonnant le phénotype immunogénique de la tumeur au cours de son développement. Le système immunitaire joue donc un double rôle dans les relations complexes existantes entre l'hôte et la tumeur. L'objet de cette revue est de faire le point sur ces différentes interactions en détaillant les acteurs du système immunitaire impliqués dans la mise en place d'une réponse immunitaire antitumorale. Mots clés : Immunologie -CancerImmunosurveillanceImmunology and cancer: antitumoral immune response Abstract: Cancer development and the host's immune system are closely connected. It has become clear that a functional cancer immunosurveillance process exists that acts as an intrinsic tumor suppressor. However, the immune system can facilitate tumor progression, at least in part, by sculpting the immunogenic phenotype of tumors as they develop. The immune system plays a dual role in the complex relations between tumors and the host. In this review we focus on these various interactions and list the actors involve in antitumoral immune response.