Acute myeloid leukaemia cells secrete a soluble factor that inhibits T and NK cell proliferation but not cytolytic function – implications for the adoptive immunotherapy of leukaemia

• Published in: Clinical and experimental immunology Vol. 126; no. 3; pp. 403 - 411
• Main Authors: Orleans‐Lindsay, J. K., Barber, L. D., Prentice, H. G., Lowdell, M. W.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01-12-2001; Blackwell; Oxford University Press; Blackwell Science Inc
• Subjects: adoptive immunotherapy; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Applied cell therapy and gene therapy; Biological and medical sciences; Cancer Immunology; Cell Division; Cytotoxicity, Immunologic; Graft vs Leukemia Effect - immunology; graft‐versus‐leukaemia; HL-60 Cells; Humans; Immunotherapy, Adoptive; Interleukin-15 - pharmacology; Interleukin-2 - pharmacology; Isoantigens - administration & dosage; K562 Cells; Killer Cells, Natural - immunology; Killer Cells, Natural - pathology; Leukemia, Myeloid, Acute - immunology; Leukemia, Myeloid, Acute - pathology; Leukemia, Myeloid, Acute - therapy; Lymphocyte Activation; Medical sciences; Mitogens - pharmacology; Suppressor Factors, Immunologic - metabolism; T-Lymphocytes - immunology; T-Lymphocytes - pathology; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Tumor Cells, Cultured; tumour induced immunosuppression; Human; Graft versus leukemia reaction; Immune response; Cell therapy; Acute; Stem cell; Hematopoietic cell; Homograft; Cytotoxicity; Malignant hemopathy; Adoptive transfer; Natural killer cell; Immunosuppression; Treatment; Immunotherapy; T-Lymphocyte; Graft; Tumor cell; Acute myelocytic leukemia
• ISSN: 0009-9104; 1365-2249
• DOI: 10.1046/j.1365-2249.2001.01692.x

Evidence of an immune mediated graft‐versus‐leukaemia effect has led to the belief that T and NK cell based adoptive immunotherapy can constitute effective treatment for relapsed leukaemias. However, work on solid tumours has shown this strategy may be hampered, by an immune escape mechanism in which tumour secreted immunosuppressive factors compromise T and NK cell function. Indeed, acute myeloid leukaemia (AML) cells secrete immunosuppressive factors that block the synthesis of Th1 type cytokines in T cells. We demonstrate here that this immunosuppression, mediated by both HL60 AML cell line and primary AML blasts, inhibits T and NK cell proliferation but not cytolytic activity.
Supernatants from HL60 cell line and primary AML blasts inhibited T cell proliferation to mitogenic and alloantigen stimulation but had no effect on cytolytic function. Similarly, the proliferation of NK cells to IL‐2 and IL‐15 stimulation was inhibited whilst their cytolytic function, shown by lysis of AML blasts, K562 and Daudi cells remained unaffected. The failure of T and NK cells to proliferate was not due to effector cell apoptosis. Indeed, removal of lymphocytes from the immunosuppressive environment partially restored their capacity to respond to mitogenic stimulation. T cells exposed to immunosuppressive supernatants did not increase expression of mitotic inhibitory proteins that arrest cell division, thereby ruling this out as a mechanism of operation for this immunosuppression. T cell expansion requires antigen stimulation, usually provided in the form of AML blasts, therefore our data suggest that NK cells may be more practical for the immunotherapy of AML.