Abstract
To understand how cytotoxic agent-induced cancer cell death affects the immune system is of fundamental importance to stimulate immune response to counteract the high mortality due to cancer. Here we compared the immunogenicity of Primary Effusion Lymphoma (PEL) cell death induced by anticancer drug Bortezomib (Velcade) and Tyrphostin AG 490, a Janus Activated Kinase 2/signal trasducer and activator of transcription-3 (JAK2/STAT3) inhibitor. We show that both treatments were able to induce PEL apoptosis with similar kinetics and promote dendritic cells (DC) maturation. The surface expression of molecules involved in immune activation, namely calreticulin (CRT), heat shock proteins (HSP) 90 and 70 increased in dying cells. This was correlated with DC activation. We found that PEL cell death induced by Bortezomib was more effective in inducing uptake by DC compared to AG 490 or combination of both drugs. However the DC activation induced by all treatments was completely inhibited when these cells were pretreated with a neutralizing antiboby directed against the HSP90/70 and CRT common receptor, CD91. The activation of DC by Bortezomib and AG 490 treated PEL cells, as seen in the present study, might have important implications for a combined chemo and immunotherapy in such patients.
Highlights
Primary effusion lymphoma (PEL) is a non-Hodgkin’s lymphoma characterized by lymphomatous effusions of pleural, pericardial and abdominal cavities [1]
Diverse tumor cell type or the same tumor cell type dying in response to different cell death triggers can result in apoptosis that elicits a different activation of immune response [7,8].The immunizing properties of killed tumor cells depend on the ability of cytotoxic agents to render their death immunogenic so that the immune system can be alerted to the presence of a tumor
BC3 were treated with Bortezomib and AG 490, alone or in combination and the induction of apoptosis was assessed by the percentage of Annexin V positive cells after 6, 12 and 24 hours treatment
Summary
Primary effusion lymphoma (PEL) is a non-Hodgkin’s lymphoma characterized by lymphomatous effusions of pleural, pericardial and abdominal cavities [1]. The characteristics of the immunogenic cell death are the traslocation of the endoplasmic reticulum-resident CRT to the plasma membrane, followed by release or surface expression of HSP70 and HSP90 molecules that either provide a direct immunogenic signal for DC activation or act as vehicles for peptide antigen exposure [9]. Our results show that both drugs were able to induce BC3 apoptosis and DC maturation through traslocation of CRT and HSPs on the surface of dying cells. A previous study has highlighted the importance of chaperone traslocation in vivo showing that, displaying the same level of apoptosis or necrosis, indolent non-Hodkgin’s lymphoma cells obtained from patients with a good response to chemotherapy were better able to translocate CRT and HSP90 to the cell surface than those of nonresponders [15]. Beside the CRT and HSPs traslocation, the caspase activation usually present in the apoptotic process is important for the immunogenicity of the cell death [16]
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