A high‐throughput RNAi screen for detection of immune‐checkpoint molecules that mediate tumor resistance to cytotoxic T lymphocytes
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 therape...
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| Main Authors: | , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
17 February 2015
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| In: |
EMBO molecular medicine
Year: 2015, Volume: 7, Issue: 4, Pages: 450-463 |
| ISSN: | 1757-4684 |
| DOI: | 10.15252/emmm.201404414 |
| Online Access: | Verlag, kostenfrei, Volltext: http://dx.doi.org/10.15252/emmm.201404414 Verlag, kostenfrei, Volltext: http://embomolmed.embopress.org/content/7/4/450 
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| Author Notes: | 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 |
| Summary: | 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. |
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| Item Description: | Gesehen am 22.11.2017 |
| Physical Description: | Online Resource |
| ISSN: | 1757-4684 |
| DOI: | 10.15252/emmm.201404414 |