Calreticulin exposure dictates the immunogenicity of cancer cell death.

INSERM U848, 39 Rue Camille-Desmoulins, F-94805 Villejuif, France.
Nature Medicine (Impact Factor: 28.05). 02/2007; 13(1):54-61. DOI: 10.1038/nm1523
Source: PubMed

ABSTRACT 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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    ABSTRACT: Calreticulin is recognized as one of pivotal damage-associated molecular pattern (DAMP) molecules alerting the host of the presence of distressed cells. In this role, calreticulin becomes exposed on the surface of tumor cells treated by several types of cancer therapy including photodynamic therapy (PDT). The goal of the present study was to examine the potential of externally added calreticulin for augmenting antitumor effect mediated by PDT. Recombinant calreticulin was found to bind to mouse SCCVII tumor cells treated by PDT. Compared to the outcome with PDT alone, cure-rates of SCCVII tumors grown in immunocompetent C3H/HeN mice were elevated when calreticulin (0.4 mg/mouse) was injected peritumorally immediately after PDT. Such therapeutic gain with PDT plus calreticulin combination was not obtained with SCCVII tumors growing in immunodeficient NOD-scid mice. In PDT vaccine protocol, where PDT-treated SCCVII cells are used for vaccination of SCCVII tumor-bearing mice, adding recombinant calreticulin to cells before their injection produced improved therapeutic effect. The expression of calreticulin gene was reduced in PDT-treated cells, while no changes were observed with the expression of this gene in tumor, liver, and spleen tissues in PDT vaccine-treated mice. These findings reveal that externally added recombinant calreticulin can boost antitumor response elicited by PDT or PDT-generated vaccines, and can thus serve as an effective adjuvant for cancer treatment with PDT and probably other cancer cell stress-inducing modalities.
    Frontiers in Oncology 02/2015; 5(February):15. DOI:10.3389/fonc.2015.00015
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    ABSTRACT: It is now admitted that the immune system plays a major role in tumor control. Besides the existence of tumor-specific T cells and B cells, many studies have demonstrated that high numbers of tumor-infiltrating lymphocytes are associated with good clinical outcome. In addition, not only the density but also the organization of tumor-infiltrating immune cells has been shown to determine patient survival. Indeed, more and more studies describe the development within the tumor microenvironment of tertiary lymphoid structures (TLS), whose presence has a positive impact on tumor prognosis. TLS are transient ectopic lymphoid aggregates displaying the same organization and functionality as canonical secondary lymphoid organs, with T-cell-rich and B-cell-rich areas that are sites for the differentiation of effector and memory T cells and B cells. However, factors favoring the emergence of such structures within tumors still need to be fully characterized. In this review, we survey the state of the art of what is known about the general organization, induction, and functionality of TLS during chronic inflammation, and more especially in cancer, with a particular focus on the B-cell compartment. We detail the role played by TLS B cells in anti-tumor immunity, both as antigen-presenting cells and tumor antigen-specific antibody-secreting cells, and raise the question of the capacity of chemotherapeutic and immunotherapeutic agents to induce the development of TLS within tumors. Finally, we explore how to take advantage of our knowledge on TLS B cells to develop new therapeutic tools.
    Frontiers in Immunology 02/2015; 6:67. DOI:10.3389/fimmu.2015.00067
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    ABSTRACT: This year the American association for cancer research meeting was held in San Diego. "Harnessing breakthroughs and targeting cures" was the title of this meeting where the major recent scientific data on cancer research were discussed. This year was undoubtedly the year of immunotherapy and immunology of tumors. With the aim of sharing the data presented at this congress, AERIO (Association d'Enseignement et de Recherche des Internes d'Oncologie) and Oncologie joined to propose a digest of this outstanding congress. Of course, exhaustivity is not an objective of this type of digest which reflects the choices of young researchers and physicians, with the help of the editorial board, among the multiple themes and researches presented and discussed during this meeting. Tumor immunology and immunotherapy data from the congress are reported. Moreover, autophagy, microbiome, liquid biopsy, tumoral heterogeneity, and cancer stem cells data from this congress are reported, as a reflection of the diversity of this meeting and cancer research. From a clinical point of view, new targets and molecules and the new design of clinical trial are also reported.
    Oncologie 08/2014; 16(7-8):341-366. DOI:10.1007/s10269-014-2414-y · 0.08 Impact Factor

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