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

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

  • Mol Cancer. 2023 Aug 15;22(1):136. doi: 10.1186/s12943-023-01833-8.
Paweł Stachura # 1 2,  Wei Liu # 1,  Haifeng C Xu 1,  Agnès Wlodarczyk 2,  Olivia Stencel 2,  Piyush Pandey 1,  Melina Vogt 2,  Sanil Bhatia 2,  Daniel Picard 2 3 4 5,  Marc Remke 2 3 4 5,  Karl S Lang 6,  Dieter Häussinger 7,  Bernhard Homey 8,  Philipp A Lang 1,  Arndt Borkhardt 2,  Aleksandra A Pandyra 9 10 11
Affiliations

Affiliations

  • 1 Department of Molecular Medicine II, Medical Faculty, Heinrich-Heine-University, Universitätsstraße 1, 40225, Düsseldorf, Germany.
  • 2 Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Center of Child and Adolescent Health, Heinrich-Heine-University, Moorenstrasse 5, 40225, Düsseldorf, Germany.
  • 3 Division of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 4 Partner Site Essen/Düsseldorf, German Consortium for Translational Cancer Research (DKTK), Düsseldorf, Germany.
  • 5 Department of Neuropathology, Medical Faculty, Heinrich-Heine University, Moorenstrasse 5, Düsseldorf, 40225, Germany.
  • 6 Institute of Immunology, Medical Faculty, University of Duisburg-Essen, Hufelandstrasse 55, 45147, Essen, Germany.
  • 7 Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, Heinrich-Heine-University, Moorenstrasse 5, Düsseldorf, 40225, Germany.
  • 8 Department of Dermatology, Medical Faculty, Heinrich-Heine-University, Moorenstrasse 5, Düsseldorf, 40225, Germany.
  • 9 Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Center of Child and Adolescent Health, Heinrich-Heine-University, Moorenstrasse 5, 40225, Düsseldorf, Germany. aleksandra.pandyra@uni-duesseldorf.de.
  • 10 Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Venusberg-Campus 1, 53127, Bonn, Germany. aleksandra.pandyra@uni-duesseldorf.de.
  • 11 German Center for Infection Research (DZIF), Partner Site Bonn-Cologne, Bonn, Germany. aleksandra.pandyra@uni-duesseldorf.de.
  • # Contributed equally.
PMID: 37582744 DOI: 10.1186/s12943-023-01833-8
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.

Keywords

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

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