Factor of time in dendritic cell (DC) maturation : short-term activation of DCs significantly improves type 1 cytokine production and T cell responses

Poženel, Primož (author), Zajc, Kaja (author), Švajger, Urban (author)

Dendritic cells (DCs) have been intensively studied in correlation to tumor immunology and for the development DC-based cancer vaccines. Here, we present the significance of the temporal aspect of DC maturation for the most essential subsequent timepoint, namely at interaction with responding T cells or after CD40-Ligand restimulation. Mostly, DC maturation is still being achieved by activation processes which lasts 24 h to 48 h. We hypothesized this amount of time is excessive from a biological standpoint and could be the underlying cause for functional exhaustion. Indeed, shorter maturation periods resulted in extensive capacity of monocyte-derived DCs to produce inflammatory cytokines after re-stimulation with CD40-Ligand. This effect was most evident for the primary type 1 polarizing cytokine, IL-12p70. This capacity reached peak at 6 h and dropped sharply with longer exposure to initial maturation stimuli (up to 48 h). The 6 h maturation protocol reflected superiority in subsequent functionality tests. Namely, DCs displayed twice the allostimulatory capacity of 24 h- and 48 h-matured DCs. Similarly, type 1 T cell response measured by IFN-γ production was 3-fold higher when CD4$^+$ T cells had been stimulated with shortly matured DC and over 8-fold greater in case of CD8$^+$ T cells, compared to longer matured DCs. The extent of melanoma-specific CD8$^+$ cytotoxic T cell induction was also greater in case of 6 h DC maturation. The major limitation of the study is that it lacks in vivo evidence, which we aim to examine in the future. Our findings show an unexpectedly significant impact of temporal exposure to activation signals for subsequent DC functionality, which we believe can be readily integrated into existing knowledge on in vitro/ex vivo DC manipulation for various uses. We also believe this has important implications for DC vaccine design for future clinical trials.

• Language: English
• Keywords: dendritic cells, maturation, vaccines, cytotoxic T cells, cancer, anti-tumor responses
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2024
• Number of pages: Str. 14 str.
• Numbering: Vol. 22, art. 541
• PID: 20.500.12556/RUL-158422
• UDC: 615.371:616-006
• ISSN on article: 1479-5876
• DOI: 10.1186/s12967-024-05368-4
• COBISS.SI-ID: 198061059
• Publication date in RUL: 10.06.2024

Record is a part of a journal

• Title: Journal of translational medicine
• Shortened title: J. transl. med.
• Publisher: BioMed Central
• ISSN: 1479-5876
• COBISS.SI-ID: 513978393

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: dendritične celice, zorenje, citotoksične celice T, protitumorski odzivi, rak (medicina), cepiva

Projects

• Funder: ARIS - Slovenian Research and Innovation Agency
• Project number: J1-4417
• Name: Razvoj novih nizkomolekularnih modulatorjev Tollu podobnih receptorjev 7 in 8 za imunoterapijo raka

• Funder: ARIS - Slovenian Research and Innovation Agency
• Project number: P3-0371
• Name: Človeške matične celice-napredno zdravljenje s celicami III