TY  - JOUR
AU  - Stachura, Paweł
AU  - Liu, Wei
AU  - Xu, Haifeng C
AU  - Wlodarczyk, Agnès
AU  - Stencel, Olivia
AU  - Pandey, Piyush
AU  - Vogt, Melina
AU  - Bhatia, Sanil
AU  - Picard, Daniel
AU  - Remke, Marc
AU  - Lang, Karl S
AU  - Häussinger, Dieter
AU  - Homey, Bernhard
AU  - Lang, Philipp A
AU  - Borkhardt, Arndt
AU  - Pandyra, Aleksandra A
TI  - Unleashing T cell anti-tumor immunity: new potential for 5-Nonloxytryptamine as an agent mediating MHC-I upregulation in tumors.
JO  - Molecular cancer
VL  - 22
IS  - 1
SN  - 1476-4598
CY  - London
PB  - Biomed Central
M1  - DKFZ-2023-01662
SP  - 136
PY  - 2023
AB  - 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.
KW  - 5-Nonyloxytryptamine (5-NL) (Other)
KW  - Antigen-presenting machinery (Other)
KW  - CD8+ T cells (Other)
KW  - Cold tumors (Other)
KW  - Immunotherapy (Other)
KW  - cAMP response element-binding protein (CREB) (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:37582744
DO  - DOI:10.1186/s12943-023-01833-8
UR  - https://inrepo02.dkfz.de/record/278581
ER  -