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NOX4 inhibition potentiates immunotherapy by overcoming cancer-associated fibroblast-mediated CD8 T-cell exclusion from tumours

Ford, Kirsty, Hanley, Christopher J., Mellone, Massimiliano, Szyndralewiez, Cedric, Heitz, Freddy, Wiesel, Philippe, Wood, Oliver, Machado, Maria, Lopez, Maria-Antoinette, Ganesan, Anusha-Preethi, and others. (2020) NOX4 inhibition potentiates immunotherapy by overcoming cancer-associated fibroblast-mediated CD8 T-cell exclusion from tumours. Cancer Research, . ISSN 0008-5472. E-ISSN 1538-7445. (doi:10.1158/0008-5472.CAN-19-3158) (KAR id:80335)

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Determining mechanisms of resistance to PD-1/PD-L1 immune checkpoint immunotherapy is key to developing new treatment strategies. Cancer-associated fibroblasts (CAF) have many tumor-promoting functions and promote immune evasion through multiple mechanisms, but as yet, there are no CAF-specific inhibitors clinically available. Here we generated CAF-rich murine tumor models (TC1, MC38, 4T1) to investigate how CAF influence the immune microenvironment and affect response to different immunotherapy modalities (anti-cancer vaccination; TC1, [HPV E7 DNA vaccine];PD-1, MC38) and found that CAFs broadly suppressed response by specifically excluding CD8+ T-cells from tumors (not CD4+ T-cells or macrophages); CD8+ T-cell exclusion was similarly present in CAF-rich human tumors. RNA sequencing of CD8+ T-cells from CAF-rich murine tumors and immunochemistry analysis of human tumors identified significant upregulation of CTLA-4 in the absence of other exhaustion markers; inhibiting CTLA-4 with a non-depleting antibody overcame the CD8+ T-cell exclusion effect without affecting T-regs. We then examined the potential for CAF targeting, focusing on the ROS-producing enzyme NOX4, which is upregulated by CAF in many human cancers, and compared this to TGF-062;1 inhibition, a key regulator of the CAF phenotype. siRNA knockdown or pharmacological inhibition (GKT137831 [Setanaxib]) of NOX4 'normalized' CAF to a quiescent phenotype and promoted intratumoral CD8+T-cell infiltration, overcoming the exclusion effect; TGF-062;1 inhibition could prevent, but not reverse, CAF differentiation. Finally, NOX4 inhibition restored immunotherapy response in CAF-rich tumors. These findings demonstrate that CAF-mediated immunotherapy resistance can be effectively overcome through NOX4 inhibition, and could improve outcome in a broad range of cancers.

Item Type: Article
DOI/Identification number: 10.1158/0008-5472.CAN-19-3158
Subjects: Q Science
Divisions: Divisions > Division of Natural Sciences > Biosciences
Depositing User: Tim Fenton
Date Deposited: 02 Mar 2020 15:15 UTC
Last Modified: 04 Mar 2024 18:50 UTC
Resource URI: (The current URI for this page, for reference purposes)

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