title: Chronic lymphocytic leukemia cells induce defective LFA-1-directed T-cell motility by altering Rho GTPase signaling that is reversible with lenalidomide.
abstract: T lymphocytes have an essential role in adaptive immunity and rely on the activation of integrin lymphocyte function-associated antigen-1 (LFA-1) to mediate cell arrest and migration. In cancer, malignant cells modify the immune microenvironment to block effective host antitumor responses. We show for the first time that CD4 and CD8 T cells from patients with chronic lymphocytic leukemia (CLL) exhibit globally impaired LFA-1-mediated migration and that this defect is mediated by direct tumor cell contact. We show that following the coculture of previously healthy T cells with CLL cells, subsequent LFA-1 engagement leads to altered Rho GTPase activation signaling by downregulating RhoA and Rac1, while upregulating Cdc42. Of clinical relevance, repair of this T-cell defect was demonstrated using the immunomodulatory drug lenalidomide, which completely rescued adhesion and motility function by restoring normal Rho GTPase activation signaling. Our report identifies a novel cancer immune evasion mechanism whereby tumor cells induce Rho GTPase signaling defects in T cells that prevent appropriate LFA-1 activation and motility. We believe these findings identify important biomarkers and highlight the clinical utility of immunotherapy to rescue normal T-cell function in CLLs that are likely to have relevance in other cancers.
authors: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom. a.ramsay@qmul.ac.uk
authors: Alan G
authors: AG
authors: Ramsay
authors: Rachel
authors: R
authors: Evans
authors: Shahryar
authors: S
authors: Kiaii
authors: Lena
authors: L
authors: Svensson
authors: Nancy
authors: N
authors: Hogg
authors: John G
authors: JG
authors: Gribben
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D018920:Coculture Techniques; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology; D000077269:Lenalidomide; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000378:metabolism; D061251:Primary Cell Culture; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D044767:Ubiquitin-Protein Ligases; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; C502543:CRBN protein, human; D007155:Immunologic Factors; D016169:Lymphocyte Function-Associated Antigen-1; C107953:RAC1 protein, human; C066737:RHOA protein, human; D013792:Thalidomide; D044767:Ubiquitin-Protein Ligases; D010447:Peptide Hydrolases; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D000077269:Lenalidomide