Chronic lymphocytic leukemia T cells show impaired immunological synapse formation that can be reversed with an immunomodulating drug.
Cancer is associated with immune deficiency, but the biologic basis of this is poorly defined. Here we demonstrate that impaired actin polymerization results in CD4+ and CD8+ T cells from patients with chronic lymphocytic leukemia (CLL) exhibiting defective immunological synapse formation with APCs. Although this synapse dysfunction was in part a result of the CLL cells having poor APC function, defective actin polymerization was also identified in T cells from patients with CLL. We further demonstrate that, following contact with CLL cells, defects in immune synapse formation were induced in healthy allogeneic T cells. This required direct contact and was inhibited by blocking adhesion molecules on CLL B cells. In T cells from patients with CLL and in T cells from healthy individuals that had been in contact with CLL cells, recruitment of key regulatory proteins to the immune synapse was inhibited. Treatment of autologous T cells and CLL cells with the immunomodulating drug lenalidomide resulted in improved synapse formation. These results define what we believe to be a novel immune dysfunction in T cells from patients with CLL that has implications for both autologous and allogeneic immunotherapy approaches and identifies repair of immune synapse defects as an essential step in improving cancer immunotherapy approaches.
Institute of Cancer, Centre for Medical Oncology, Barts and The London School of Medicine, University of London, London, United Kingdom.
Alan G
AG
Ramsay
Amy J
AJ
Johnson
Abigail M
AM
Lee
Güllü
G
Gorgün
Rifca
R
Le Dieu
William
W
Blum
John C
JC
Byrd
John G
JG
Gribben
D000199:Actins / Q000378:metabolism; D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects / Q000276:immunology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D007376:Interleukin-2 / Q000378:metabolism; D000077269:Lenalidomide; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D018089:Superantigens / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D013792:Thalidomide / Q000031:analogs & derivatives / Q000494:pharmacology
D000199:Actins; D000970:Antineoplastic Agents; D007155:Immunologic Factors; D007376:Interleukin-2; D016169:Lymphocyte Function-Associated Antigen-1; D008840:Microfilament Proteins; D011518:Proto-Oncogene Proteins; D011948:Receptors, Antigen, T-Cell; D018089:Superantigens; C490393:Tcl1 protein, mouse; D013792:Thalidomide; D011505:Protein-Tyrosine Kinases; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D000077269:Lenalidomide