Abstract
BackgroundThe tumor cell lysate-pulsed, dendritic cell (DC)-based cancer vaccine approaches are being actively evaluated for application to cancer immunotherapy, hopefully at a personalized medicine base. There is apparently an emerging technical problem however, the lack of highly efficacious potency in activation of patient’s DCs for T-cell priming and the associated process for presenting tumor immunogenicity.MethodsOne strategy to address this is to consider the manipulation of the tumor immunogenic cells death (ICD) complex ex-vivo for maximal activation of DC efficacy. In our previous study we showed that phytochemical shikonin (SK) can drastically enhance ICD activity in mouse tumor cells treated ex-vivo, and the resultant tumor cell lysate (TCL) can effectively augment such SK-TCL pulsed DC vaccine activity in vivo in anti-tumor activities. In this study, we investigated the specifics and the multi-functional effects of various damaged associated molecular pattern (DAMP) components of the ICD complex for their participation, roles and potential cross talks in activating DCs, as measured by five different functional assays.ResultsAmong three DAMPs tested, HSP70 and CRT mediate a key role in SK-TCL-induced DC immunity for both CD4+ and CD8+ T cell proliferations in vitro. HSP70 is the most important component, followed by CRT, then HMGB1 in facilitating DC immunity on suppressing metastasis of mouse 4 T1 mammary tumors and prolonging survival in test mice. Only HSP70, but not CRT or HMGB1, is effective for the suppression of both granulocytic and monocytic MDSC populations in vivo. Both HSP70 and HMGB1, but not CRT, are essential in activating the expression of three key ICD molecules-associated receptors on test DCs. Each of the three test ICD proteins can exhibit a distinguishable pattern in stimulating the expression of four key chemokines in test DCs.ConclusionOur findings on the differential roles or effect of various ICD components in activating vaccinated DCs may help formulate new strategies for future cancer vaccine designs.
Highlights
Simultaneous changes of damage-associated molecular patterns (DAMPs) associated with immunogenicity, including glucose-related protein (GRP), heat shock proteins (HSP), calreticulin (CRT), high mobility group box 1 (HMGB1) and others are well characterized in mechanisms for immunogenic cell death (ICD) [1]
We further showed that in combination with pathogenassociated molecular patterns (PAMPs), such as toll-like receptors, shikonin-induced tumor cells lysate (SK-tumor cell lysate (TCL)) can activate dendritic cell (DC) to phenotypic and functional maturation, which in turn increased the cytotoxic T lymphocyte activity contributing to efficacious retardation of tumor growth and prolonged the survival of test mice [8]
Effect of shikonin-treated 4 T1 tumor cell lysates (SK-TCL) on DC-activated T-cell proliferation To evaluate the efficacy of using shikonin-induced immunogenic cell death (ICD) in tumor cells to enhance DC-mediated T-cell proliferation activity, test DCs were stimulated in culture with shikonin-treated 4 T1 tumor cell lysates (SK-TCL), and the effect of the resultant DCs on Tcell proliferation was tested by mixed lymphocyte reaction (MLR) assay
Summary
Simultaneous changes of damage-associated molecular patterns (DAMPs) associated with immunogenicity, including glucose-related protein (GRP), heat shock proteins (HSP), calreticulin (CRT), high mobility group box 1 (HMGB1) and others are well characterized in mechanisms for immunogenic cell death (ICD) [1]. Toll-like receptor 4 (TLR4) is essential for sensing DAMPs, as well as the resultant activation of DCs and the induction of Th1 response [4, 5]. Treatment with chemotherapeutic agents such as anthracyclines and bortezomib is known to induce a premortem stress response that exerts immunostimulatory effects after the exposure of heat shock proteins such as HSP70 and HSP90 on the surface of dying cancer cells [5]. Some conventional chemotherapeutics (e.g., the nucleoside analog gemcitabine) as well as targeted agents [e.g., the epidermal growth factor receptor (EGFR) inhibitor, erlotinib] result in increased levels of class I or class II MHC molecules on the tumor cell surface, effectively facilitating their recognition by the immune system [6, 7]. There is apparently an emerging technical problem the lack of highly efficacious potency in activation of patient’s DCs for T-cell priming and the associated process for presenting tumor immunogenicity
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