A high‐throughput RNAi screen for detection of immune‐checkpoint molecules that mediate tumor resistance to cytotoxic T lymphocytes

• Verfasst von: Khandelwal, Nisit [VerfasserIn]
• Verfasst von: Breinig, Marco [VerfasserIn]
• Verfasst von: Poschke, Isabel [VerfasserIn]
• Verfasst von: Offringa, Rienk [VerfasserIn]
• Titel: A high‐throughput RNAi screen for detection of immune‐checkpoint molecules that mediate tumor resistance to cytotoxic T lymphocytes
• Verf.angabe: Nisit Khandelwal, Marco Breinig, Tobias Speck, Tillmann Michels, Christiane Kreutzer, Antonio Sorrentino, Ashwini Kumar Sharma, Ludmila Umansky, Heinke Conrad, Isabel Poschke, Rienk Offringa, Rainer König, Helga Bernhard, Arthur Machlenkin, Michael Boutros and Philipp Beckhove
• E-Jahr: 2015
• Jahr: 17 February 2015
• Umfang: 14 S.
• Fussnoten: Gesehen am 22.11.2017
• Titel Quelle: Enthalten in: European Molecular Biology OrganizationEMBO molecular medicine
• Ort Quelle: [London] : Nature Publishing Group UK, 2009
• Jahr Quelle: 2015
• Band/Heft Quelle: 7(2015), 4, Seite 450-463
• ISSN Quelle: 1757-4684
• DOI: doi:10.15252/emmm.201404414
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: cancer immunotherapy
• Sach-SW: immune suppression
• Sach-SW: RNAi screen
• K10plus-PPN: 1565606345

Abstract

The success of T cell‐based cancer immunotherapy is limited by tumor's resistance against killing by cytotoxic T lymphocytes (CTLs). Tumor‐immune resistance is mediated by cell surface ligands that engage immune‐inhibitory receptors on T cells. These ligands represent potent targets for therapeutic inhibition. So far, only few immune‐suppressive ligands have been identified. We here describe a rapid high‐throughput siRNA‐based screening approach that allows a comprehensive identification of ligands on human cancer cells that inhibit CTL‐mediated tumor cell killing. We exemplarily demonstrate that CCR9, which is expressed in many cancers, exerts strong immune‐regulatory effects on T cell responses in multiple tumors. Unlike PDL1, which inhibits TCR signaling, CCR9 regulates STAT signaling in T cells, resulting in reduced T‐helper‐1 cytokine secretion and reduced cytotoxic capacity. Moreover, inhibition of CCR9 expression on tumor cells facilitated immunotherapy of human tumors by tumor‐specific T cells in vivo. Taken together, this method allows a rapid and comprehensive determination of immune‐modulatory genes in human tumors which, as an entity, represent the ‘immune modulatome’ of cancer.