| Autor: |
Paweł Stachura, Wei Liu, Haifeng C. Xu, Agnès Wlodarczyk, Olivia Stencel, Piyush Pandey, Melina Vogt, Sanil Bhatia, Daniel Picard, Marc Remke, Karl S. Lang, Dieter Häussinger, Bernhard Homey, Philipp A. Lang, Arndt Borkhardt, Aleksandra A. Pandyra |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
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| Zdroj: |
Molecular Cancer, Vol 22, Iss 1, Pp 1-20 (2023) |
| Druh dokumentu: |
article |
| ISSN: |
1476-4598 |
| DOI: |
10.1186/s12943-023-01833-8 |
| Popis: |
Abstract Background 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. Methods 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. Results 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. Conclusions This study demonstrates novel therapeutic opportunities for augmenting immune responses in poorly immunogenic tumors. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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