Obeid, M. et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nature Med. 13, 54-61

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Nature Medicine (Impact Factor: 27.36). 02/2007; 13(1):54-61. DOI: 10.1038/nm1523
Source: PubMed


Anthracyclin-treated tumor cells are particularly effective in eliciting an anticancer immune response, whereas other DNA-damaging agents such as etoposide and mitomycin C do not induce immunogenic cell death. Here we show that anthracyclins induce the rapid, preapoptotic translocation of calreticulin (CRT) to the cell surface. Blockade or knockdown of CRT suppressed the phagocytosis of anthracyclin-treated tumor cells by dendritic cells and abolished their immunogenicity in mice. The anthracyclin-induced CRT translocation was mimicked by inhibition of the protein phosphatase 1/GADD34 complex. Administration of recombinant CRT or inhibitors of protein phosphatase 1/GADD34 restored the immunogenicity of cell death elicited by etoposide and mitomycin C, and enhanced their antitumor effects in vivo. These data identify CRT as a key feature determining anticancer immune responses and delineate a possible strategy for immunogenic chemotherapy.

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    • "In order to prime durable anti-cancer immune responses against irradiated tumor cells, professional antigen presenting cells need to receive inflammatory signals that can promote their maturation and functional capacity to cross-present antigenic peptides to T cells. Radiation-induced tumor cell death has been suggested to achieve this by signaling the translocation of the endoplasmic reticulum (ER)-resident protein complex, calreticulin (CRT)/ ERp57 to the cell membrane [54]; an " eat-me " signal that is thought to be required for dendritic cell recognition and engulfment of dying tumor cells. Calreticulin expression is an immunogenic signature associated with low-dose radiation-induced apoptosis. "
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    ABSTRACT: Over the last decade there has been a dramatic shift in the focus of cancer research towards understanding how the body's immune defenses can be harnessed to promote the effectiveness of cytotoxic anti-cancer therapies. The ability of ionizing radiation to elicit anti-cancer immune responses capable of controlling tumor growth has led to the emergence of promising combination-based radio-immunotherapeutic strategies for the treatment of cancer. Herein we review the immunoadjuvant properties of localized radiation therapy and discuss how technological advances in radio-oncology and developments in the field of tumor-immunotherapy have started to revolutionize the therapeutic application of radiotherapy. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Cancer Letters 01/2015; 368(2). DOI:10.1016/j.canlet.2015.01.009 · 5.62 Impact Factor
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    • "In fact, it is well known that the peculiar patchy distribution of ecto-CRT plays an important role in the phagocytosis-modulating efficacies and outcomes. Ecto-CRT, by co-localizing with PtdS on plasma membrane [40], functions as an “eat me” signal to favor phagocytosis in different cell lines such as fibroblasts, neutrophils and Jurkat T cells of dead cells by dendritic cells and macrophages that, consequently, initiate immune response [6], [41]. The CRT-PtdS domains on the apoptotic cells surface are very efficient “eat-me” signals that stimulate phagocytosis by segregating away the “don’t eat me” CD47 signals and by activating the internalization receptors, LRP (LDL-Receptor-related Protein, also known as CD91 receptor), present on phagocytes. "
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    ABSTRACT: The new concept of Immunogenic Cell Death (ICD), associated with Damage Associated Molecular Patterns (DAMPs) exposure and/or release, is recently becoming very appealing in cancer treatment. In this context, PhotoDynamic Therapy (PDT) can give rise to ICD and to immune response upon dead cells removal. The list of PhotoSensitizers (PSs) able to induce ICD is still short and includes Photofrin, Hypericin, Foscan and 5-ALA. The goal of the present work was to investigate if Rose Bengal Acetate (RBAc), a powerful PS able to trigger apoptosis and autophagy, enables photosensitized HeLa cells to expose and/or release pivotal DAMPs, i.e. ATP, HSP70, HSP90, HMGB1, and calreticulin (CRT), that characterize ICD. We found that apoptotic HeLa cells after RBAc-PDT exposed and released, early after the treatment, high amount of ATP, HSP70, HSP90 and CRT; the latter was distributed on the cell surface as uneven patches and co-exposed with ERp57. Conversely, autophagic HeLa cells after RBAc-PDT exposed and released HSP70, HSP90 but not CRT and ATP. Exposure and release of HSP70 and HSP90 were always higher on apoptotic than on autophagic cells. HMGB1 was released concomitantly to secondary necrosis (24 h after RBAc-PDT). Phagocytosis assay suggests that CRT is involved in removal of RBAc-PDT generated apoptotic HeLa cells. Altogether, our data suggest that RBAc has all the prerequisites (i.e. exposure and/or release of ATP, CRT, HSP70 and HSP90), that must be verified in future vaccination experiments, to be considered a good PS candidate to ignite ICD. We also showed tha CRT is involved in the clearance of RBAc photokilled HeLa cells. Interestingly, RBAc-PDT is the first cancer PDT protocol able to induce the translocation of HSP90 and plasma membrane co-exposure of CRT with ERp57.
    PLoS ONE 08/2014; 9(8):e105778. DOI:10.1371/journal.pone.0105778 · 3.23 Impact Factor
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    • "Correspondingly, the activation of the immune system through specific immune-based therapies is efficacious for the treatment of some cancers. This includes antibodies that target cancer cells, such as Rituximab [63] and Trastuzumab [64], as well as antibodies or drugs that modulate immunostimulatory or immunoinhibitory signals [65-67], such as anti-CTLA-4 [68] and anti-PD-L1 [69]. The combination of conventional chemotherapy with targeted immune therapy has emerged as an effective approach for the treatment of some cancers. "
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    07/2014; 2(1):24. DOI:10.1186/2051-1426-2-24
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