title: Immune checkpoint inhibitors enhance cytotoxicity of cytokine-induced killer cells against human myeloid leukaemic blasts.
abstract: We studied whether blockade of inhibitory receptors on cytokine-induced killer (CIK) cells by immune checkpoint inhibitors could increase its anti-tumour potency against haematological malignancies. CIK cultures were generated from seven normal donors and nine patients with acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL) or multiple myeloma (MM). The inhibitory receptors B and T lymphocyte attenuator, CD200 receptor, lymphocyte activation gene-3 (LAG-3) and T cell immunoglobulin and mucin-domain-containing-3 (TIM-3) were present at variable percentages in most CIK cultures, while cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed death-1 (PD-1) and killer cell immunoglobulin-like receptors (KIR2DL1/2/3) were expressed at low level in most cultures. Without blockade, myeloid leukaemia cells were susceptible to autologous and allogeneic CIK-mediated cytotoxicity. Blockade of KIR, LAG-3, PD-1 and TIM-3 but not CTLA-4 resulted in remarkable increase in killing against these targets, even in those with poor baseline cytotoxicity. ALL and MM targets were resistant to CIK-mediated cytotoxicity, and blockade of receptors did not increase cytotoxicity to a meaningful extent. Combination of inhibitors against two receptors did not further increase cytotoxicity. Interestingly, potentiation of CIK killing by blocking antibodies was not predicted by expression of receptors on CIK and their respective ligands on the targets. Compared to un-activated T and NK cells, blockade potentiated the cytotoxicity of CIK cells to a greater degree and at a lower E:T ratio, but without significant increase in cytotoxicity against normal white cell. Our findings provide the basis for clinical trial combining autologous CIK cells with checkpoint inhibitors for patients with AML.
authors.affiliation: Department of Haematology, Singapore General Hospital, Level 3, Academia, 20, College Road, Singapore, 169856, Singapore.
authors.forename: Su Li
authors.initials: SL
authors.lastname: Poh
authors.affiliation: Department of Haematology, Singapore General Hospital, Level 3, Academia, 20, College Road, Singapore, 169856, Singapore. linn.yeh.ching@sgh.com.sg.
authors.forename: Yeh Ching
authors.identifier: http://orcid.org/0000-0001-8098-2590
authors.initials: YC
authors.lastname: Linn
mesh_terms: D000208:Acute Disease; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D000954:Antigens, Surface / Q000276:immunology / Q000378:metabolism; D060908:CTLA-4 Antigen / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D055612:Cytokine-Induced Killer Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D003601:Cytotoxicity Tests, Immunologic / Q000379:methods; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000276:immunology*; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D007951:Leukemia, Myeloid / Q000276:immunology* / Q000473:pathology; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000276:immunology*; D064446:Orexin Receptors; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000276:immunology / Q000378:metabolism; D054340:Receptors, KIR / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; C477337:CD200R1 protein, human; D060908:CTLA-4 Antigen; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; D008565:Membrane Proteins; D064446:Orexin Receptors; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D011956:Receptors, Cell Surface; D054340:Receptors, KIR
keywords: Cytokine-induced killer cells; Immune checkpoint inhibitors; Inhibitory receptor and ligand; Myeloid leukaemia