title: Clinical implications of antigen transfer mechanisms from malignant to dendritic cells. exploiting cross-priming.
abstract: Expansion and activation of cytolytic T lymphocytes bearing high-affinity T-cell receptors specific for tumor antigens is a major goal of active cancer immunotherapy. Physiologically, T cells receive promitotic and activating signals from endogenous professional antigen-presenting cells (APC) rather than directly from malignant cells. This phenomenon fits with the broader concept of cross-presentation that earlier was demonstrated for minor histocompatibility and viral antigens. Many mechanisms have been found to be capable of transferring antigenic material from malignant cells to APC so that it can be processed and subsequently presented by MHC class I molecules expressed on APC. Dendritic cells (DC) are believed to be the most relevant APC mediating cross-presentation because they can take up antigens from apoptotic, necrotic, and even intact tumor cells. There exist specific molecular mechanisms that ensure this transfer of antigenic material: 1) opsonization of apoptotic bodies; 2) receptors for released heat shock proteins carrying peptides processed intracellularly; 3) Fc receptors that uptake immunocomplexes and immunoglobulins; and 4) pinocytosis. DC have the peculiar capability of reentering the exogenously captured material into the MHC class I pathway. Exploitation of these pieces of knowledge is achieved by providing DC with complex mixtures of tumor antigens ex vivo and by agents and procedures that promote infiltration of malignant tissue by DC. The final outcome of DC cross-presentation could be T-cell activation (cross-priming) but also, and importantly, T-cell tolerance contingent upon the activation/maturation status of DC. Artificial enhancement of tumor antigen cross-presentation and control of the immune-promoting status of the antigen-presenting DC will have important therapeutic implications in the near future.
authors.affiliation: Centro de Investigación Médica Aplicada (CIMA), School of Medicine and Cell Therapy Area (Clínica Universitaria), University of Navarra, Pamplona, Spain.
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Arina
authors.forename: Iñigo
authors.initials: I
authors.lastname: Tirapu
authors.forename: Carlos
authors.initials: C
authors.lastname: Alfaro
authors.forename: Mercedes
authors.initials: M
authors.lastname: Rodríguez-Calvillo
authors.forename: Guillermo
authors.initials: G
authors.lastname: Mazzolini
authors.forename: Susana
authors.initials: S
authors.lastname: Inogés
authors.forename: Ascensión
authors.initials: A
authors.lastname: López
authors.forename: Esperanza
authors.initials: E
authors.lastname: Feijoo
authors.forename: Maurizio
authors.initials: M
authors.lastname: Bendandi
authors.forename: Ignacio
authors.initials: I
authors.lastname: Melero
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000502:physiology*; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods; D009369:Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy; D009360:Neoplastic Cells, Circulating / Q000276:immunology*