Abstract
Antigen cross-presentation is a crucial step in the assembly of an antitumor immune response leading to activation of naïve CD8 T cells. This process has been extensively used in clinical trials, in which dendritic cells generated in vitro are loaded with tumor antigens and then autotransplanted to the patients. Recently, the use of autologous transplant of dendritic cells fused with dying tumor cells has demonstrated good results in clinical studies. In this work, we generated a similar process in vivo by treating mice with dead tumor cells [cell bodies (CBs)] expressing the fusogenic protein of the infectious salmon anemia virus (ISAV). ISAV fusion protein retains its fusogenic capability when is expressed on mammalian cells in vitro and the CBs expressing it facilitates DCs maturation, antigen transfer by antigen-presenting cells, and increase cross-presentation by DCs in vitro. Additionally, we observed in the melanoma model that CBs with or without ISAV fusion protein reduce tumor growth in prophylactic treatment; however, only ISAV expressing CBs showed an increase CD4 and CD8 cells in spleen. Overall, our results suggest that CBs could be used as a complement with other type of strategies to amplify antitumor immune response.
Highlights
Dendritic cells are the most important antigen-presenting cells (APCs); they are present at trace levels in the tissues and stand for less than 0.5% of circulating leukocytes
To determine whether infectious salmon anemia virus (ISAV) fusion protein retains its fusogenic activity when expressed in mammalian cells, HEK293 and MDCK cells were stably transfected with the open reading frame of ISAV segment 5, which corresponds to the fusogenic protein
We found that after 48–72 h post-passage, non-transfected HEK293 and transfected HEK293-ISAV showed morphological changes associated with cell fusion (Figure 1A); HEK293-ISAV presents a higher number of fused cells (HEK293 = 0.38 ± 0.23 vs. HEK293-ISAV = 1.08 ± 0.26; Figure 1B)
Summary
Dendritic cells are the most important antigen-presenting cells (APCs); they are present at trace levels in the tissues and stand for less than 0.5% of circulating leukocytes These cells activate naïve CD8 T cells by delivering antigens through cross-priming and this particular characteristic has been used in cancer immunotherapy clinical trials [1]. Immunotherapy using dendritic cells in vitro requires a large amount of cells, these are obtained by differentiating monocytes or CD34+ progenitors with granulocyte-macrophage colony-stimulating factor and IL-4 [2] These cells can be loaded with tumor antigens and multiple techniques have been used for this purpose, including tumor-extracted RNA transfection, pulsing with tumor lysates, apoptotic body induction, peptides, tumor-derived exosomes, and heterokaryon-induction from tumor-dendritic cell fusion [3]. Animals inoculated with dying tumor cells undergoing ICD (induced by oxaliplatins) elicit tumor-specific immune responses protecting the animals against subsequent tumor challenges [8]
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