%0 Journal Article
%A Stachura, Paweł
%A Liu, Wei
%A Xu, Haifeng C
%A Wlodarczyk, Agnès
%A Stencel, Olivia
%A Pandey, Piyush
%A Vogt, Melina
%A Bhatia, Sanil
%A Picard, Daniel
%A Remke, Marc
%A Lang, Karl S
%A Häussinger, Dieter
%A Homey, Bernhard
%A Lang, Philipp A
%A Borkhardt, Arndt
%A Pandyra, Aleksandra A
%T Unleashing T cell anti-tumor immunity: new potential for 5-Nonloxytryptamine as an agent mediating MHC-I upregulation in tumors.
%J Molecular cancer
%V 22
%N 1
%@ 1476-4598
%C London
%I Biomed Central
%M DKFZ-2023-01662
%P 136
%D 2023
%X New therapies are urgently needed in melanoma, particularly in late-stage patients not responsive to immunotherapies and kinase inhibitors. To uncover novel potentiators of T cell anti-tumor immunity, we carried out an ex vivo pharmacological screen and identified 5-Nonyloxytryptamine (5-NL), a serotonin agonist, as increasing the ability of T cells to target tumor cells.The pharmacological screen utilized lymphocytic choriomeningitis virus (LCMV)-primed splenic T cells and melanoma B16.F10 cells expressing the LCMV gp33 CTL epitope. In vivo tumor growth in C57BL/6 J and NSG mice, in vivo antibody depletion, flow cytometry, immunoblot, CRISPR/Cas9 knockout, histological and RNA-Seq analyses were used to decipher 5-NL's immunomodulatory effects in vitro and in vivo.5-NL delayed tumor growth in vivo and the phenotype was dependent on the hosts' immune system, specifically CD8+ T cells. 5-NL's pro-immune effects were not directly consequential to T cells. Rather, 5-NL upregulated antigen presenting machinery in melanoma and other tumor cells in vitro and in vivo without increasing PD-L1 expression. Mechanistic studies indicated that 5-NL's induced MHC-I expression was inhibited by pharmacologically preventing cAMP Response Element-Binding Protein (CREB) phosphorylation. Importantly, 5-NL combined with anti-PD1 therapy showed significant improvement when compared to single anti-PD-1 treatment.This study demonstrates novel therapeutic opportunities for augmenting immune responses in poorly immunogenic tumors.
%K 5-Nonyloxytryptamine (5-NL) (Other)
%K Antigen-presenting machinery (Other)
%K CD8+ T cells (Other)
%K Cold tumors (Other)
%K Immunotherapy (Other)
%K cAMP response element-binding protein (CREB) (Other)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:37582744
%R 10.1186/s12943-023-01833-8
%U https://inrepo02.dkfz.de/record/278581