title: The Rho-ROCK pathway as a new pathological mechanism of innate immune subversion in chronic myeloid leukaemia.
abstract: CD1d-restricted invariant natural killer T (iNKT) cells are believed to play a key role in cancer immune surveillance, and are functionally deficient in patients with chronic myeloid leukaemia (CML). Herein, we have hypothesized that this defect might originate from BCR-ABL-dependent dysfunctions in myeloid dendritic cells (mDCs). Indeed, flow cytometry and confocal microscopy revealed that cell surface expression of CD1d was downregulated in CML mDCs, relative to healthy donor (HD) controls. The decreased cell surface display of CD1d could not be ascribed to defective mDC differentiation, as attested by normal expression of HLA-DR and the CD86 maturation marker. On the other hand, reduced membrane expression was not associated with decreased intracytoplasmic levels of CD1d or its mRNA transcripts, consistent with intracellular retention. In vitro treatment of CML mDCs with the Rho-associated protein kinase (ROCK) inhibitor Y-27632 partially restored both cell surface CD1d expression and CD1d-mediated antigen presentation, whereas it had no effect on HD mDCs. An inhibitor of BCR-ABL tyrosine kinase (TK), imatinib mesylate (IM), had no such activity. Similar recovery of CD1d expression occurred with fasudil, another ROCK inhibitor that is commonly used in clinical trials. Our data support the conclusion that BCR-ABL-dependent ROCK, but not TK, is involved in CD1d downregulation. We propose that ROCK, which is most likely activated by the DH/PH domain of BCR-ABL, mediates iNKT-cell immune subversion in CML patients by downregulating CD1d expression on CML mDCs. Our study reveals the ROCK-mDC axis as a new potential target to restore immune surveillance in patients with CML, offering new therapeutic perspectives for CML treatment. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
authors: INSERM U1082, Poitiers, France.|Université de Poitiers, Poitiers, France.
authors: Sara
authors: S
authors: Basbous
authors: INSERM U1082, Poitiers, France.
authors: Anaïs
authors: A
authors: Levescot
authors: CHU de Poitiers, Poitiers, France.
authors: Nathalie
authors: N
authors: Piccirilli
authors: CHU de Poitiers, Poitiers, France.|Service d'Hématologie et d'Oncologie Biologique, Poitiers, France.
authors: Françoise
authors: F
authors: Brizard
authors: Université de Poitiers, Poitiers, France.|CHU de Poitiers, Poitiers, France.|Service d'Hématologie et d'Oncologie Biologique, Poitiers, France.|INSERM-CIC 1402, Poitiers, France.
authors: François
authors: F
authors: Guilhot
authors: INSERM-CIC 1402, Poitiers, France.
authors: Lydia
authors: L
authors: Roy
authors: Laboratoire STIM CNRS-ERL7368, Poitiers, France.
authors: Nicolas
authors: N
authors: Bourmeyster
authors: INSERM U1082, Poitiers, France.|Université de Poitiers, Poitiers, France.|CHU de Poitiers, Poitiers, France.|Service d'Immunologie et Inflammation, Poitiers, France.
authors: Jean-Marc
authors: JM
authors: Gombert
authors: INSERM U1082, Poitiers, France. andre.herbelin@inserm.fr.|Université de Poitiers, Poitiers, France. andre.herbelin@inserm.fr.|CHU de Poitiers, Poitiers, France. andre.herbelin@inserm.fr.
authors: André
authors: A
authors: Herbelin
mesh_terms: D000577:Amides / Q000494:pharmacology; D055610:Antigens, CD1d / Q000276:immunology*; D002454:Cell Differentiation; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016044:Fusion Proteins, bcr-abl / Q000276:immunology; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology; D007113:Immunity, Innate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D022423:Myeloid Cells / Q000201:enzymology / Q000276:immunology; D055611:Natural Killer T-Cells / Q000201:enzymology / Q000276:immunology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000276:immunology*
chemical_list: D000577:Amides; D055610:Antigens, CD1d; C526877:CD1D protein, human; D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C108830:Y 27632; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; C515851:ROCK1 protein, human; C515852:ROCK2 protein, human; D054460:rho-Associated Kinases
keywords: CD1d; Rho-associated protein kinase; chronic myeloid leukaemia; dendritic cells; iNKT cells