Intratumoural administration of dendritic cells: hostile environment and help by gene therapy.
Like paratroopers in special operations, dendritic cells (DCs) can be deployed behind the enemy borders of malignant tissue to ignite an antitumour immune response. 'Cross-priming T cell responses' is the code name for their mission, which consists of taking up antigen from transformed cells or their debris, migrating to lymphoid tissue ferrying the antigenic cargo, and meeting specific T cells. This must be accomplished in such an immunogenic manner that specific T lymphocytes would mount a robust enough response as to fully reject the malignancy. To improve their immunostimulating activity, local gene therapy can be very beneficial, either by transfecting DCs with genes enhancing their performance, or by preparing tumour tissue with pro-inflammatory mediators. In addition, endogenous DCs from the tumour host can be attracted into the malignant tissue following transfection of certain chemokine genes into tumour cells. On their side, tumour stroma and malignant cells set up a hostile immunosuppressive environment for artificially released or attracted DCs. This milieu is usually rich in transforming growth factor-beta, vascular endothelial growth factor, and IL-10, -6 and -8, among other substances that diminish DC performance. Several molecular strategies are being devised to interfere with the immunosuppressive actions of these substances and to further enhance the level of anticancer immunity achieved after artificial release of DCs intratumourally.
Huarte
Eduardo
E
University of Navarra School of Medicine, Gene Therapy Unit, Centro Investigación Médica Aplicada (CIMA), Avda/Pio XII,55, 31080 Pamplona, Spain.
Tirapu
Iñigo
I
Arina
Ainhoa
A
Vera
María
M
Alfaro
Carlos
C
Murillo
Oihana
O
Palencia
Belén
B
Busto
Victoria
V
Marín
Verónica
V
Mazzolini
Guillermo
G
Melero
Ignacio
I
D000818:Animals; D003713:Dendritic Cells / Q000276:immunology*; D004777:Environment; D005818:Genetic Engineering / Q000379:methods; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000276:immunology*