4.7 Article

Unleashing T cell anti-tumor immunity: new potential for 5-Nonloxytryptamine as an agent mediating MHC-I upregulation in tumors

Journal

MOLECULAR CANCER
Volume 22, Issue 1, Pages -

Publisher

BMC
DOI: 10.1186/s12943-023-01833-8

Keywords

CD8(+) T cells; Immunotherapy; Antigen-presenting machinery; 5-Nonyloxytryptamine (5-NL); Cold tumors; cAMP response element-binding protein (CREB)

Ask authors/readers for more resources

This study identifies a drug called 5-NL that can enhance the ability of T cells to target tumor cells, and it shows improved efficacy when used in combination with PD-1 antibody treatment.
BackgroundNew 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.MethodsThe 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.Results5-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.ConclusionsThis study demonstrates novel therapeutic opportunities for augmenting immune responses in poorly immunogenic tumors.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.7
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available