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
| Autor: | John G. Gribben, Alan G. Ramsay, Rewas Fatah, Andrew Clear |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
rho GTP-Binding Proteins
Immunological Synapses Antibodies Neoplasm T cell Chronic lymphocytic leukemia T-Lymphocytes Immunology Antigen-Presenting Cells Down-Regulation Antineoplastic Agents Biology Ligands Biochemistry Polymerization Synapse Immune system Antigen Antigens CD medicine Humans Immunologic Factors Lenalidomide Immune Evasion Immunobiology Immunosuppression Therapy Cell Biology Hematology medicine.disease Prognosis Leukemia Lymphocytic Chronic B-Cell Actins Cell biology Thalidomide Up-Regulation Enzyme Activation Leukemia medicine.anatomical_structure biology.protein Antibody Signal transduction Signal Transduction |
| Zdroj: | Blood. 120(7) |
| ISSN: | 1528-0020 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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