2. Academic Validation
  3. Amitriptyline revitalizes ICB response via dually inhibiting Kyn/Indole and 5-HT pathways of tryptophan metabolism in ovarian cancer

Amitriptyline revitalizes ICB response via dually inhibiting Kyn/Indole and 5-HT pathways of tryptophan metabolism in ovarian cancer

  • iScience. 2024 Nov 28;27(12):111488. doi: 10.1016/j.isci.2024.111488.
Junyang Li 1,  Bingjie Mei 1,  Lu Feng 2,  Xiaoxin Wang 1,  Dengfeng Wang 1,  Jianming Huang 3,  Guonan Zhang 1
Affiliations

Affiliations

  • 1 Department Gynecological Oncology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu 610041, China.
  • 2 Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China.
  • 3 Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu 610041, China.
PMID: 39759009 DOI: 10.1016/j.isci.2024.111488
Abstract

Reprogramming tryptophan metabolism (TRP) may be able to overcome immunosuppression and restore the Immune Checkpoint blockade (ICB) response in patients with epithelial ovarian Cancer (EOC) resistant to ICB therapy because TRP metabolism is involved in the kynurenine/indole and serotonin pathways of tryptophan metabolism. Herein, employing amitriptyline (AMI), an antagonist of TLR4 and Serotonin Transporter (SERT), we revealed that AMI remodels the immunological landscape of EOC. In particular, AMI lowered the expression of IDO1, IL-4I1, and PD-L1, the quantity of KYN and indoles, and the level of immunosuppressive immune cells MDSC, Tregs, and CD8+CD39+/PD-1+ T cell. AMI boosted the killing potential of anti-PD-1-directed CD8+T cells and worked in concert with PD-1 inhibitors to suppress tumor growth and to prolong the survival of EOC-bearing mice. This work highlights AMI as an effective regulator of ICB response by manipulating EOC cell TRP metabolism, indicating it could be a potential strategy for improving EOC ICB therapy.

Keywords

Cancer; Immune response; Microenvironment.

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