Abstract
While the primary purpose of radiotherapy (RT) is the elimination of cancer cells by inducing DNA-damage, considerable evidence emerges that anti-neoplastic effects extend beyond mere tumor cell killing. These secondary effects are based on activation of dendritic cells (DCs) via induction of antitumoral immune reactions. However, there is an ongoing debate whether or not irradiation of the DCs themselves may negatively affect their maturation and functionality. Human monocytes were irradiated with different absorbed doses (1 × 15 Gy relative biological effectiveness (RBE), 5 × 2 Gy (RBE), 1 × 0.5 Gy (RBE)) with photons, protons and carbon ions. Differentiation and maturation of DCs were assessed by staining of corresponding cell surface molecules and functional analysis of irradiated DCs was based on in vitro analysis of phagocytosis, migration and IL-12 secretion. Irradiation of CD14-positive DCs did not alter surface phenotypes of immature DCs and mature DCs. Not only differentiation, but also functionality of immature DCs regarding phagocytosis, migration and IL-12 secretion capacity was not negatively influenced through RT with photons, protons or carbon ions as well as with different dose levels. After proton irradiation migratory capacity of immature DCs was increased. Our experiments reveal that phenotypic maturation of DCs remains unchanged after RT with different fractionations and after irradiation with particle therapy. Unaffected functionality (phagocytosis, migration and cytokine secretion) after RT of DCs indicated possible persistent potential for inducing adaptive immune response. Additional effects on the immunogenic potential of DCs will be investigated by further functional assays.
Highlights
Dendritic cells (DCs) are professional antigenpresenting cells (APCs) which play a crucial role in initiating tumor immunity
The costimulatory molecules CD80 and CD86 are increasingly expressed on the cell surface and subsequent binding of CD80/CD86 molecule to the CD28 molecule expressed on T cells delivers, in addition to T-cell receptor (TCR) engagement, the co-stimulatory signal for successful T cell activation followed by clonal expansion of the antigen-specific T cell population
Irradiation of monocytes on day 0 with photons, protons and carbon ions mostly showed no significant change in the expression profile of characteristic surface markers of immature monocyte-derived DCs (iMO-DCs) (CD14−, CD209+, HLA-DR+) compared to the untreated control on day 7
Summary
Dendritic cells (DCs) are professional antigenpresenting cells (APCs) which play a crucial role in initiating tumor immunity. Immature DCs (iDCs) reside in peripheral tissue, where they are activated and matured upon encounter of pathogens Phagocytosed antigens such as bacteria, viruses or damaged (tumor) tissue are processed by the immunoproteasome in the iDC and presented as epitopes on major histocompatibility complex (MHC) molecules expressed by the DC. Cross-presentation of TAA leads to activation of cytotoxic T-lymphocytes, playing a pivotal role in adaptive immune response and immunogenic cell death [6,7]. During this maturation process of DCs, Interleukin-12 (IL-12) is produced and plays an important role in the activation of natural killer cells and T lymphocytes [8,9]. The costimulatory molecules CD80 and CD86 are increasingly expressed on the cell surface and subsequent binding of CD80/CD86 molecule to the CD28 molecule expressed on T cells delivers, in addition to T-cell receptor (TCR) engagement, the co-stimulatory signal for successful T cell activation followed by clonal expansion of the antigen-specific T cell population
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