title: Multiple inhibitory ligands induce impaired T-cell immunologic synapse function in chronic lymphocytic leukemia that can be blocked with lenalidomide: establishing a reversible immune evasion mechanism in human cancer.
abstract: Cancer immune evasion is an emerging hallmark of disease progression. We have demonstrated previously that impaired actin polymerization at the T-cell immunologic synapse is a global immune dysfunction in chronic lymphocytic leukemia (CLL). Direct contact with tumor cells induces defective actin polarization at the synapse in previously healthy T cells, but the molecules mediating this dysfunction were not known. In the present study, we show via functional screening assays that CD200, CD270, CD274, and CD276 are coopted by CLL cells to induce impaired actin synapse formation in both allogeneic and autologous T cells. We also show that inhibitory ligand-induced impairment of T-cell actin dynamics is a common immunosuppressive strategy used by both hematologic (including lymphoma) and solid carcinoma cells. This immunosuppressive signaling targets T-cell Rho-GTPase activation. Of clinical relevance, the immunomodulatory drug lenalidomide prevented the induction of these defects by down-regulating tumor cell-inhibitory molecule expression. These results using human CLL as a model cancer establish a novel evasion mechanism whereby malignant cells exploit multiple inhibitory ligand signaling to down-regulate small GTPases and lytic synapse function in global T-cell populations. These findings should contribute to the design of immunotherapeutic strategies to reverse T-cell tolerance in cancer.
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom. a.ramsay@qmul.ac.uk
authors.forename: Alan G
authors.initials: AG
authors.lastname: Ramsay
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Clear
authors.forename: Rewas
authors.initials: R
authors.lastname: Fatah
authors.forename: John G
authors.initials: JG
authors.lastname: Gribben
mesh_terms: D000199:Actins / Q000378:metabolism; D000912:Antibodies, Neoplasm / Q000494:pharmacology / Q000627:therapeutic use; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology; D015703:Antigens, CD / Q000276:immunology; D000970:Antineoplastic Agents / Q000627:therapeutic use; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D057131:Immune Evasion / Q000187:drug effects*; D007155:Immunologic Factors / Q000494:pharmacology; D054992:Immunological Synapses / Q000187:drug effects* / Q000276:immunology; D007165:Immunosuppression Therapy; D000077269:Lenalidomide; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000276:immunology* / Q000503:physiopathology; D008024:Ligands; D058105:Polymerization / Q000187:drug effects; D011379:Prognosis; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology; D020741:rho GTP-Binding Proteins / Q000378:metabolism
chemical_list: D000199:Actins; D000912:Antibodies, Neoplasm; D015703:Antigens, CD; D000970:Antineoplastic Agents; D007155:Immunologic Factors; D008024:Ligands; D013792:Thalidomide; D020741:rho GTP-Binding Proteins; D000077269:Lenalidomide