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Therapeutic targeting of thioredoxin reductase 1 causes ferroptosis while potentiating anti-PD-1 efficacy in head and neck cancer.
- Source :
-
Chemico-biological interactions [Chem Biol Interact] 2024 May 25; Vol. 395, pp. 111004. Date of Electronic Publication: 2024 Apr 16. - Publication Year :
- 2024
-
Abstract
- Head and neck squamous cell carcinoma (HNSCC) faces low response rates to anti-PD-1 immunotherapies, highlighting the need for enhanced treatment strategies. Auranofin, which inhibits thioredoxin reductase (TrxR) through its gold-based composition, has shown potential in cancer treatment. It targets the TrxR system, essential for safeguarding cells from oxidative stress. The overproduction of TrxR in cancerous cells supports their proliferation. However, auranofin's interference with this system can upset the cellular redox equilibrium, boost levels of reactive oxygen species, and trigger the death of cancer cells. This study is the first to highlight TXNRD1 as a crucial factor contributing to resistance to anti-PD-1 treatment in HNSCC. In this study, we identified targetable regulators of resistance to immunotherapy-induced ferroptosis in HNSCC. We observed a link of thioredoxin reductase 1 (TXNRD1) with tumoral PD-L1 expression and ferroptosis suppression in HNSCC. Moreover, HNSCC tumors with aberrant TXNRD1 expression exhibited a lack of PD-1 response, NRF2 overexpression, and PD-L1 upregulation. TXNRD1 inhibition promoted ferroptosis in HNSCC cells with NRF2 activation and in organoid tumors derived from patients lacking a PD-1 response. Mechanistically, TXNRD1 regulated PD-L1 transcription and maintained the redox balance by binding to ribonucleotide reductase regulatory subunit M2 (RRM2). TXNRD1 expression disruption sensitized HNSCC cells to anti-PD-1-mediated Jurkat T-cell activation, promoting tumor killing through ferroptosis. Moreover, TXNRD1 inhibition through auranofin cotreatment synergized with anti-PD-1 therapy to potentiate immunotherapy-mediated ferroptosis by mediating CD8 <superscript>+</superscript> T-cell infiltration and downregulating PD-L1 expression. Our findings indicate that targeting TXNRD1 is a promising therapeutic strategy for improving immunotherapy outcomes in patients with HNSCC.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2024 Elsevier B.V. All rights reserved.)
- Subjects :
- Humans
Cell Line, Tumor
Animals
Squamous Cell Carcinoma of Head and Neck drug therapy
Squamous Cell Carcinoma of Head and Neck metabolism
Squamous Cell Carcinoma of Head and Neck pathology
Mice
Programmed Cell Death 1 Receptor metabolism
Programmed Cell Death 1 Receptor antagonists & inhibitors
Immune Checkpoint Inhibitors pharmacology
Immune Checkpoint Inhibitors therapeutic use
NF-E2-Related Factor 2 metabolism
Reactive Oxygen Species metabolism
Thioredoxin Reductase 1 metabolism
Thioredoxin Reductase 1 antagonists & inhibitors
Head and Neck Neoplasms drug therapy
Head and Neck Neoplasms metabolism
Head and Neck Neoplasms pathology
Ferroptosis drug effects
Auranofin pharmacology
B7-H1 Antigen metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1872-7786
- Volume :
- 395
- Database :
- MEDLINE
- Journal :
- Chemico-biological interactions
- Publication Type :
- Academic Journal
- Accession number :
- 38636790
- Full Text :
- https://doi.org/10.1016/j.cbi.2024.111004