Gene therapy using genetically modified lymphocytes targeting VEGFR-2 inhibits the growth of vascularized syngenic tumors in mice. as the dominant mechanism involved in the rejection of allografts and tumors in animal models. Thus, attempts to develop effective immunotherapies in the human have emphasized the generation of T cells capable of recognizing antigens expressed by cancers. The T-cell receptor (TCR) is the means by which lymphocytes can sense the presence of antigens in their environment with exquisite specificity. Individual lymphocytes bear numerous copies of a single TCR with a unique antigen-binding site. Each person possesses over 1011 lymphocytes, thus constituting an immense repertoire of unique TCR. The wide range of antigen specificities in TCR is due to variation in the amino acid sequence at the antigen-binding site, assembled in the developing lymphocyte by somatic DNA recombination of the variable regions encoding the receptor protein chains. T-cells recognize short peptides derived from proteins degraded in nucleated cells and presented in the groove of major histocompatibility complex (MHC) molecules at the cell surface. The genomic instability and aberrant gene expression in cancer cells are thus expected to result in expression of peptides immunologically distinct from normal cells, Dp44mT in quality and in quantity. The first cancer antigen to be characterized at a genetic and molecular level and recognized by T cells was MAGE-1 [1]. Since then, hundreds of peptides derived from tumors have been identified and shown to be expressed by solid tumors of various histologies and restricted to presentation on different subclasses of MHC molecules [2]. Tumor-associated antigens fall into several major categories: 1) overexpressed normal proteins (eg, carcinoembryonic antigen (CEA) or non mutated p53); 2) non-mutated differentiation antigens (eg, MART-1, overexpressed in melanoma and found in normal melanocytes); 3) cancer-testis antigens (CTA), consisting of non-mutated genes expressed during fetal development, then silent in normal adult tissues and reactivated in cancer cells across multiple malignancies (eg, MAGE and NY-ESO); 4) mutated antigens, unique to a single tumor or shared by a group of tumors (eg, BRAF with the V600E mutation in melanoma and other solid tumors, or EGFRvIII in glioblastoma). Despite the fact that tumor-associated antigens recognized by T cells have been described, solid cancers in humans grow and disseminate in immune competent hosts. Two main reasons, that are not mutually exclusive, explain this reality: a) most cancers are weakly or not immunogenic, hence the frequency of tumor-reactive lymphocytes is low or null in most patients; b) immunologic mechanisms of T cell anergy or tolerance, or immunosuppressive factors, either systemic or in the tumor microenvironment thwart anti-tumor immune reactions. Table 1 summarizes general mechanisms described to result in cancer progression despite a competent immune system. Since cancer antigens are commonly nonmutated self-proteins, the naturally occurring pool of T cells able to recognize those self-antigens do so with low avidity, otherwise they would have been deleted during negative selection in the thymus during development. If a T cell is capable of reacting to a self-antigen in tissues and tumors, mechanisms involved in the prevention of autoimmunity are at play and referred to as peripheral tolerance. The fate of T cells able to strongly recognize altered-self antigens, like mutated cancer antigens, is less clear. However, since the tumor can participate in immune suppression and tolerance at the tumor site in multiple ways, anti-cancer cytotoxic T cells are expected to lose cytotoxic functions and proliferative capacity, and may be driven to apoptosis. The lack of appropriate co-stimulation signals provided to na?ve T cells by antigen presenting cells found in an immature or inactivated state has also been proposed as a mechanism to explain the Dp44mT poor lytic and proliferative capacity of T cells upon second encounters with tumor antigens. Table Rabbit Polyclonal to Cyclin L1 1 General mechanisms that can inhibit anti-tumor immune reaction in cancer Dp44mT patients Immune factorsLow or null frequency of anti-tumor T cells assays have suggested the existence of Treg and MDSC in cancer patients, but studies are in their infancy. The heterogeneity of the transformed cells that constitute a tumor mass also contribute to tumor progression, since many cancer cells may go unrecognized by the immune system while partial tumor destruction by T cells occurs. This natural selection of less immunogenic tumor cells over time has been coined tumor immunoediting and is mainly supported in animal models [7, 8]. Despite all mechanisms able to inhibit anti-tumor immune reaction and the uncertainty of naturally occurring immune responses to solid cancers, T cell-mediated immunity plays the predominant role in mediating the rejection.