Tumor-derived antioxidants suppress immunity by depriving T cells of reactive oxygen species
Abstract
Reactive oxygen species (ROS) promote genomic instability and fuel oncogenic signaling in cancer, but antioxidant therapies have so far failed to improve, or worsen, cancer outcomes. Emerging data suggest that T cells depend on ROS for signal transduction. In this study, we show that tumors exploit this dependency, releasing antioxidant enzymes into the tumor environment to suppress T cell–mediated antitumor immunity. The interstitial fluid of tumors possesses potent antioxidant activity, associated with enrichment of the antioxidant enzyme peroxiredoxin 1 (PRDX1). Extracellular PRDX1 deprives T cells of ROS, preventing oxidative inactivation of phosphatases required for T cell receptor–driven kinase signaling and effector function. Prdx1 is up-regulated upon cancer immunoediting, and loss of PRDX1 within tumors enhances antitumor immunity and immunotherapy responses. These findings define a redox-dependent mechanism of tumor immunosuppression that is potentially amenable to therapeutic intervention.
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Authors: Alexander J. Wesolowski, Ardon M. Pillay, Panagiota Vardaka, Rabab Nasrallah, RANDY GREAVES, Housaiyin Li, Iliana Loffreda, Chelsea Jenkins, Andrew M. James, Alica Nübling, Chris Ward, Teresa von Linde, Alberto G. Conti, Sheue‐Fen Tzeng, Layla Dahmani, Alexander C. Evans, Sarah K. Whiteside, Yumi Yamashita-Kanemaru, Charlotte J. Imianowski, Jie Yang, Ignacio Moraga, Jack Chapman, Aws Al-Deka, Klaus Okkenhaug, Michael P. Murphy, Bartłomiej Świątczak, Geoffrey Guittard, Enrico Lugli, Lukas Flatz, Ping‐Chih Ho, Robert Eil, Rahul Roychoudhuri
Institutions: University of Oxford, Oregon Health & Science University, University of Dundee, University of Tübingen, University of Cambridge, Taipei Medical University, University of Lausanne, IRCCS Humanitas Research Hospital, Babraham Institute, Centre de Recherche en Cancérologie de Marseille, MRC Mitochondrial Biology Unit, Ludwig Cancer Research