Inhibition of host NOX1 blocks tumor growth and enhances checkpoint inhibitor-based immunotherapy.

Autor:	Stalin J; Department of Pathology and Immunology, Medical Faculty, University of Geneva, Geneva, Switzerland jimmy.stalin@unifr.ch.; Department of Oncology, Microbiology and Immunology, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland., Garrido-Urbani S; Department of Pathology and Immunology, Medical Faculty, University of Geneva, Geneva, Switzerland., Heitz F; Genkyotex S.A Forum 2, Archamps Technopole, Saint-Julien-en-Genevois, France., Szyndralewiez C; Genkyotex S.A Forum 2, Archamps Technopole, Saint-Julien-en-Genevois, France., Jemelin S; Department of Pathology and Immunology, Medical Faculty, University of Geneva, Geneva, Switzerland., Coquoz O; Department of Oncology, Microbiology and Immunology, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland., Ruegg C; Department of Oncology, Microbiology and Immunology, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland curzio.ruegg@unifr.ch., Imhof BA; Department of Pathology and Immunology, Medical Faculty, University of Geneva, Geneva, Switzerland beat.imhof@unige.ch.; Medicity Research Laboratory, University of Turku, Turku, Finland.
Jazyk:	angličtina
Zdroj:	Life science alliance [Life Sci Alliance] 2019 Jun 27; Vol. 2 (4). Date of Electronic Publication: 2019 Jun 27 (Print Publication: 2019).
DOI:	10.26508/lsa.201800265
Abstrakt:	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. (© 2019 Stalin et al.)
Databáze:	MEDLINE
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