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NOX4 Inhibition Potentiates Immunotherapy by Overcoming Cancer-Associated Fibroblast-Mediated CD8 T-cell Exclusion from Tumors

Ford, Kirsty ; Hanley, Christopher J ; Mellone, Massimiliano ; Szyndralewiez, Cedric ; Heitz, Freddy ; Wiesel, Philippe ; Wood, Oliver ; Machado, Maria ; Lopez, Maria-Antoinette ; Ganesan, Anusha-Preethi ; Wang, Chuan ; Chakravarthy, Ankur ; Fenton, Tim R ; King, Emma V ; Vijayanand, Pandurangan ; Ottensmeier, Christian H ; Al-Shamkhani, Aymen ; Savelyeva, Natalia ; Thomas, Gareth J

Cancer research (Chicago, Ill.), 2020-05, Vol.80 (9), p.1846-1860 [Periódico revisado por pares]

United States

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  • Título:
    NOX4 Inhibition Potentiates Immunotherapy by Overcoming Cancer-Associated Fibroblast-Mediated CD8 T-cell Exclusion from Tumors
  • Autor: Ford, Kirsty ; Hanley, Christopher J ; Mellone, Massimiliano ; Szyndralewiez, Cedric ; Heitz, Freddy ; Wiesel, Philippe ; Wood, Oliver ; Machado, Maria ; Lopez, Maria-Antoinette ; Ganesan, Anusha-Preethi ; Wang, Chuan ; Chakravarthy, Ankur ; Fenton, Tim R ; King, Emma V ; Vijayanand, Pandurangan ; Ottensmeier, Christian H ; Al-Shamkhani, Aymen ; Savelyeva, Natalia ; Thomas, Gareth J
  • Assuntos: Animals ; Cancer-Associated Fibroblasts ; CD8-Positive T-Lymphocytes ; Cell Line, Tumor ; Humans ; Immunotherapy ; Mice ; NADPH Oxidase 4 ; Neoplasms ; Reactive Oxygen Species
  • É parte de: Cancer research (Chicago, Ill.), 2020-05, Vol.80 (9), p.1846-1860
  • Notas: ObjectType-Article-1
    SourceType-Scholarly Journals-1
    ObjectType-Feature-2
    ObjectType-Commentary-3
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  • Descrição: Determining mechanisms of resistance to αPD-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, no CAF-specific inhibitors are clinically available. Here we generated CAF-rich murine tumor models (TC1, MC38, and 4T1) to investigate how CAFs influence the immune microenvironment and affect response to different immunotherapy modalities [anticancer vaccination, TC1 (HPV E7 DNA vaccine), αPD-1, and 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 nondepleting antibody overcame the CD8 T-cell exclusion effect without affecting Tregs. 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 with TGFβ1 inhibition, a key regulator of the CAF phenotype. siRNA knockdown or pharmacologic inhibition [GKT137831 (Setanaxib)] of NOX4 "normalized" CAF to a quiescent phenotype and promoted intratumoral CD8 T-cell infiltration, overcoming the exclusion effect; TGFβ1 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. SIGNIFICANCE: NOX4 is critical for maintaining the immune-suppressive CAF phenotype in tumors. Pharmacologic inhibition of NOX4 potentiates immunotherapy by overcoming CAF-mediated CD8 T-cell exclusion. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/9/1846/F1.large.jpg. .
  • Editor: United States
  • Idioma: Inglês
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  • Realização: ABCD-USP USP   Logos de Redes Sociais: Freepik

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