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See 1 citation in EMBO Mol Med 2015 by Khandelwal:

EMBO Mol Med. 2015 Apr;7(4):450-63. doi: 10.15252/emmm.201404414.

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

Author information

1
Division of Translational Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany n.khandelwal@dkfz.de p.beckhove@dkfz.de.
2
Division of Signaling and Functional Genomics, German Cancer Research Center (DKFZ), Heidelberg, Germany Department of Cell and Molecular Biology, Faculty of Medicine Mannheim, Heidelberg University, Heidelberg, Germany.
3
Division of Translational Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
4
Division of Immunogenetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
5
Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
6
Department of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center (DKFZ) and Division of Pancreas Carcinoma Research, Surgery Clinic of Heidelberg University, Heidelberg, Germany.
7
Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC) Jena University Hospital, Jena, Germany Leibniz Institute for Natural Products Research and Infection Biology, Hans-Knöll-Institute, Jena, Germany.
8
Department of Hematology/Oncology, Klinikum Darmstadt GmbH, Darmstadt, Germany.
9
Sharett Institute of Oncology, Hadassah-Hebrew University Hospital, Jerusalem, Israel.

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.

KEYWORDS:

RNAi screen; cancer immunotherapy; immune suppression

PMID:
25691366
PMCID:
PMC4403046
DOI:
10.15252/emmm.201404414
[Indexed for MEDLINE]
Free PMC Article

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