1. Chronic lymphocytic leukemia cells induce defective LFA- 1-directed T-cell motility by altering Rho GTPase signaling that is reversible with lenalidomide.
- Author
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Ramsay, Alan G., Evans, Rachel, Kiaii, Shahryar, Svensson, Lena, Hogg, Nancy, and Gribben, John G.
- Subjects
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CHRONIC lymphocytic leukemia , *LYMPHOCYTE function-associated antigen-1 , *CELL migration , *GUANOSINE triphosphatase , *ANTINEOPLASTIC agents , *IMMUNOTHERAPY - 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 Racl,while upregulating Cdc42. Of clinical relevance, repair of this 1-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 I 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. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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