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-γ 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-κB 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.
From the *Division of Molecular and Cellular Biology, Research Institute, Sunnybrook and Women's College Health Sciences Center, Toronto, Canada; †Department of Medical Biophysics, University of Toronto, Toronto, Canada; ‡Immunology Platform, Aventis Pasteur, Toronto, Canada; §Department of Medical Oncology and Hematology, Princess Margaret Hospital, University Health Network, Toronto, Canada; ∥Department of Chemistry, Stanford University, Stanford, California; ¶Toronto-Sunnybrook Regional Cancer Center, Toronto, Canada; and **Department of Medicine, University of Toronto, Toronto, Canada.
Received for publication February 5, 2004; accepted August 4, 2004.
Supported by grants from the Leukemia Research Fund of Canada and the Ontario Cancer Research Network (to D.E.S.), the National Cancer Institute of Canada (to A.C.S.), and the National Institute of Health (CA31845 to P.A.W.).
Reprints: David Spaner, Division of Molecular and Cellular Biology, Research Institute, S-116A, Research Building, Sunnybrook and Women's College Health Sciences Center, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5 (e-mail: email@example.com).