Lymphocytes genetically modified to express tumor antigens target dendritic cells in vivo and induce antitumor immunity

Abstract

Cancer immunotherapy attempts to harness the exquisite power and specificity of the immune system for the treatment of malignancy. Although cancer cells are less immunogenic than pathogens, the immune system is clearly capable of recognizing and eliminating tumor cells. However, tumors frequently interfere with the development and function of immune responses. Thus, the challenge for immunotherapy is to use advances in cellular and molecular immunology to develop strategies that effectively and safely augment antitumor responses. An important strategy for mobilizing an anti-tumor response depends on optimal dendritic cells (DCs) activation, antigen presenting cells (APCs) normally charged with the task of ingesting infectious agents and others antigen bearing particles (including tumor cells) throughout the body’s tissues and then rushing back to nearby draining lymph nodes where T cell priming occurs. In this contest, the exploitation of the physiologic processing and presenting machinery of DCs by in vivo loading with tumor-associated antigens, may improve the immunogenic potential and clinical efficacy of DC-based cancer vaccines. In this experimental work, T lymphocytes genetically modified to express self/tumor antigens, acting as antigen carriers, efficiently target DCs in vivo in tumor-bearing mice. The infusion of TRP-2-transduced lymphocytes induces the establishment of protective immunity and long-term memory in tumor-bearing mice. The analysis of the mechanism responsible for the induction of such an immune response allowed to demonstrate that cross-presentation of the antigen mediated by the CD11c+CD8α+ DCs subset had occurred. Furthermore, results demonstrate in vivo and in vitro that DCs undergo activation upon phagocytosis of genetically modified lymphocytes (GML), a process mediated by a cell-to-cell contact mechanism independent of CD40 triggering. Targeting and activation of secondary lymphoid organ-resident DCs endowes antigen-specific T-cells with full effector functions, which ultimately increases tumor growth control and animal survival in a therapeutic tumor setting. These data clearly demonstrate that transduced T lymphocytes represent an efficient way for in vivo loading of tumor-associated antigens on DCs .