Cell biology and possible therapeutic applications of anti-CD3-activated killer-T cells (review).
Polyclonal T lymphocyte populations can be stimulated with anti-CD3 antibody to proliferate, secrete cytokines, and mediate MHC-unrestricted cytotoxic activity against a wide range of tumor target cells. Because anti-CD3-activated killer-T (AK-T) cells may be useful in the immunotherapy of human cancers, it is important to understand the signaling pathways and cell-surface structures involved in the induction and tumoricidal effector function of AK-T cells. Studies in the mouse model system have characterized the cytokines, signal transduction pathways, and costimulatory molecules involved in AK-T cell development. The recognition/adhesion and subsequent signaling events which lead to tumoricidal activity by mouse AK-T cells have also been defined. These findings, providing they translate accurately to the human system, may allow for the design of effective strategies to use AK-T cells for the treatment of human cancers. However, to date, the encouraging results obtained with anti-CD3 antibody/AK-T cell-based immunotherapies in mouse models of cancer have not been duplicated in clinical trials. The most likely explanation for this dis-appointing result is that tumor-reactive T lymphocytes in long term tumor-bearers fail to function correctly in the tumor microenvironment due to tumor-induced immune suppression and defects in key signal transduction molecules. It is clear that a detailed understanding of the inhibitory effect of established tumors on host T cells and the means to overcome tumor-induced immunosuppression are needed before anti-CD3 antibody/AK-T cell-based immunotherapies can be expected to succeed in the clinical setting.
Hoskin
D W
DW
Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia B3H 4H7, Canada.
Williams
B
B
Fitzpatrick
L
L
Makrigiannis
A P
AP
D000818:Animals; D017252:CD3 Complex / Q000276:immunology*; D016207:Cytokines / Q000502:physiology; D006801:Humans; D016219:Immunotherapy, Adoptive; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*
D017252:CD3 Complex; D016207:Cytokines