title: Functional exhaustion of CD4+T cells induced by co-stimulatory signals from myeloid leukaemia cells.
abstract: To cope with immune responses, tumour cells implement elaborate strategies such as adaptive resistance and induction of T-cell exhaustion. T-cell exhaustion has been identified as a state of hyporesponsiveness that arises under continuous antigenic stimulus. Nevertheless, contribution of co-stimulatory molecules to T-cell exhaustion in cancer remains to be better defined. This study explores the role of myeloid leukaemia-derived co-stimulatory signals on CD4+T helper (Th) cell exhaustion, which may limit anti-tumour immunity. Here, CD86 and inducible T-cell co-stimulator ligand (ICOS-LG) co-stimulatory molecules that are found on myeloid leukaemia cells supported Th cell activation and proliferation. However, under continuous stimulation, T cells co-cultured with leukaemia cells, but not with peripheral blood monocytes, became functionally exhausted. These in vitro-generated exhausted Th cells were defined by up-regulation of programmed cell death 1 (PD-1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), lymphocyte activation gene 3 (LAG3) and T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) inhibitory receptors. They were reluctant to proliferate upon re-stimulation and produced reduced amounts of interleukin-2 (IL-2), tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). Nonetheless, IL-2 supplementation restored the proliferation capacity of the exhausted Th cells. When the co-stimulation supplied by the myeloid leukaemia cells were blocked, the amount of exhausted Th cells was significantly decreased. Moreover, in the bone marrow aspirates from patients with acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS), a subpopulation of Th cells expressing PD-1, TIM-3 and/or LAG3 was identified together with CD86+and/or ICOS-LG+myeloid blasts. Collectively, co-stimulatory signals derived from myeloid leukaemia cells possess the capacity to facilitate functional exhaustion in Th cells.
authors: Department of Basic Oncology, Hacettepe University Cancer Institute, Ankara, Turkey.
authors: Didem
authors: D
authors: Ozkazanc
authors: Department of Basic Oncology, Hacettepe University Cancer Institute, Ankara, Turkey.
authors: Digdem
authors: D
authors: Yoyen-Ermis
authors: Department of Basic Oncology, Hacettepe University Cancer Institute, Ankara, Turkey.
authors: Ece
authors: E
authors: Tavukcuoglu
authors: Department of Haematology, Hacettepe University Medical Faculty, Ankara, Turkey.
authors: Yahya
authors: Y
authors: Buyukasik
authors: Department of Basic Oncology, Hacettepe University Cancer Institute, Ankara, Turkey. gunes.esendagli@lycos.com.
authors: Gunes
authors: G
authors: Esendagli
mesh_terms: D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D005260:Female; D000072597:Hepatitis A Virus Cellular Receptor 2 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000068884:Immunosenescence; D007951:Leukemia, Myeloid / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000378:metabolism*; D019139:Tumor Escape; D015854:Up-Regulation; D055815:Young Adult; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D015703:Antigens, CD; D016207:Cytokines; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D000093322:Lymphocyte Activation Gene 3 Protein; C000720326:Lag3 protein, human
keywords: T-cell immunoglobulin and mucin domain-containing protein-3; cancer; helper T cell; immune escape; interleukin-2; lymphocyte activation gene 3; programmed cell death 1