Effect of serum and antioxidants on the immunogenicity of protein kinase C-activated chronic lymphocytic leukemia cells.
Since the intrinsically poor immunogenicity of chronic lymphocytic leukemia (CLL) cells might be a key factor in allowing them to avoid immune control mechanisms, the development of methods to enhance CLL cell immunogenicity might lead to improved disease control. The ability of CLL cells to stimulate T cells was increased significantly by the protein kinase C (PKC) agonist phorbol myristic acetate (PMA). However, under serum-free conditions, PMA-activated CLL cells died within 48 hours. Antioxidants, such as 2-mercaptoethanol (2-ME), or fetal calf serum could prevent the death of these cells but caused them to enter distinct states of differentiation. In the presence of 2-ME, PMA-activated CLL cells extended dendritic-like protrusions and exhibited increased T-cell stimulatory capacity. In the presence of serum, PMA-activated CLL cells developed fewer dendrites, made less IL-10 and more IL-12 p40 mRNA transcripts, and showed an increased capacity to induce IFN-gamma production by T cells. The effects of serum on the promotion of type 1 immune responses by phorbol ester-activated CLL cells were dominant and correlated with activation of the NF-kappaB signaling pathway. Other PKC agonists, such as Bryostatin-1 and a synthetic Bryostatin analog (Picolog), had similar effects on CLL cells. The observation that CLL cells can acquire features of dendritic cells that promote type 1 immunity may find clinical application in immunotherapeutic strategies for this disease.
Hammond
Caitlin
C
Division of Molecular and Cellular Biology, Research Institute, Sunnybrook and Women's College Health Sciences Center, 2075 Bayview Avenue, Toronto, Canada M4N 3M5.
Shi
Yonghong
Y
Mena
Jenny
J
Tomic
Jelena
J
Cervi
David
D
He
Liwei
L
Millar
Amanda E
AE
Debenedette
Mark
M
Schuh
Andre C
AC
Baryza
Jeremy L
JL
Wender
Paul A
PA
Radvanyi
Laszlo
L
Spaner
David E
DE
D000328:Adult; D000368:Aged; D017951:Antigen Presentation / Q000276:immunology; D015703:Antigens, CD / Q000378:metabolism; D000956:Antigens, Viral / Q000276:immunology; D000975:Antioxidants / Q000494:pharmacology*; D054713:Bryostatins; D016923:Cell Death / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D020536:Enzyme Activators / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology; D018942:Macrolides / Q000494:pharmacology; D008297:Male; D008623:Mercaptoethanol / Q000494:pharmacology; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism*; D044967:Serum / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D015703:Antigens, CD; D000956:Antigens, Viral; D000975:Antioxidants; D054713:Bryostatins; D016895:Culture Media, Serum-Free; D020536:Enzyme Activators; D020672:I-kappa B Proteins; D018942:Macrolides; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; C572555:picolog; D016753:Interleukin-10; D018664:Interleukin-12; C046785:bryostatin 1; D008623:Mercaptoethanol; D007371:Interferon-gamma; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate