A1 Refereed original research article in a scientific journal
Inhibition of host NOX1 blocks tumor growth and enhances checkpoint inhibitor-based immunotherapy
Authors: Jimmy Stalin1, Sarah Garrido-Urbani, Freddy Heitz, Cédric Szyndralewiez, Stephane Jemelin, Oriana Coquoz, Curzio Ruegg, Beat A Imhof
Publisher: LIFE SCIENCE ALLIANCE LLC
Publication year: 2019
Journal: Life Science Alliance
Journal name in source: LIFE SCIENCE ALLIANCE
Journal acronym: LIFE SCI ALLIANCE
Article number: UNSP e201800265
Volume: 2
Issue: 4
Number of pages: 16
eISSN: 2575-1077
DOI: https://doi.org/10.26508/lsa.201800265
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/42540131
NADPH oxidases catalyze the production of reactive oxygen species and are involved in physio/pathological processes. NOX1 is highly expressed in colon cancer and promotes tumor growth. To investigate the efficacy of NOX1 inhibition as an anticancer strategy, tumors were grown in immunocompetent, immunodeficient, or NOX1-deficient mice and treated with the novel NOX1-selective inhibitor GKT771. GKT771 reduced tumor growth, lymph/angiogenesis, recruited proinflammatory macrophages, and natural killer T lymphocytes to the tumor microenvironment. GKT771 treatment was ineffective in immunodeficient mice bearing tumors regardless of their NOX-expressing status. Genetic ablation of host NOX1 also suppressed tumor growth. Combined treatment with the checkpoint inhibitor anti-PD1 antibody had a greater inhibitory effect on colon carcinoma growth than each compound alone. In conclusion, GKT771 suppressed tumor growth by inhibiting angiogenesis and enhancing the recruitment of immune cells. The antitumor activity of GKT771 requires an intact immune system and enhances anti-PD1 antibody activity. Based on these results, we propose blocking of NOX1 by GKT771 as a potential novel therapeutic strategy to treat colorectal cancer, particularly in combination with checkpoint inhibition.
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