Deubiquitinase inhibitor PR-619 potentiates colon cancer immunotherapy by inducing ferroptosis.

Abstract

A substantial number of colon cancer patients do not benefit from immunotherapy using programmed cell death 1 (PD1) antibodies. Therefore, combination therapy drugs are required to improve the efficacy of colon cancer immunotherapy. Recent studies have shown that deubiquitinases are negative regulators of anti-tumour immunity. In the present study, we investigated the effect of the deubiquitinase inhibitor PR-619 in combination with anti-PD1 for the treatment of colorectal cancer. The results revealed that co-treatment with PR-619 and anti-PD1 significantly inhibited tumour growth in tumour-bearing BALB/c mice compared to monotherapy with a single drug. In addition, PR-619/anti-PD1 combined therapy inhibited cell proliferation, promoted cell apoptosis, induced intratumor infiltration of CD8+ T cells, and enhanced the release of anti-tumour cytokines. Moreover, PR-619 induced ferroptosis in colon cancer cells, thereby inducing the release of damage-associated molecular patterns that triggered anti-tumour immunity. Finally, we discovered that PR-619 could degrade the GPX4 protein, the high expression of which was associated with poor prognosis and blocked CD8+ T cells infiltration in colon cancer. In conclusion, PR-619 may potentiate immunotherapy by inducing ferroptosis, and thereby promoting CD8+ T cells-mediated anti-tumour immunity, providing a potential strategy for colon cancer treatment.

• Authors: Jingjing Wu, Chang Liu, Tao Wang, Hua Liu, Bin Wei
• Journal: Immunology (Immunology) Vol. 170 Issue 3 Pg. 439-451 (Nov 2023) ISSN: 1365-2567 [Electronic] England
• PMID: 37526037 (Publication Type: Journal Article)
• Copyright: © 2023 John Wiley & Sons Ltd.