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1.
Int Rev Cell Mol Biol ; 328: 105-161, 2017.
Article in English | MEDLINE | ID: mdl-28069132

ABSTRACT

The spindle assembly checkpoint (SAC) is a surveillance mechanism contributing to the preservation of genomic stability by monitoring the microtubule attachment to, and/or the tension status of, each kinetochore during mitosis. The SAC halts metaphase to anaphase transition in the presence of unattached and/or untensed kinetochore(s) by releasing the mitotic checkpoint complex (MCC) from these improperly-oriented kinetochores to inhibit the anaphase-promoting complex/cyclosome (APC/C). The reversible phosphorylation of a variety of substrates at the kinetochore by antagonistic kinases and phosphatases is one major signaling mechanism for promptly turning on or turning off the SAC. In such a complex network, some kinases act at the apex of the SAC cascade by either generating (monopolar spindle 1, MPS1/TTK and likely polo-like kinase 1, PLK1), or contributing to generate (Aurora kinase B) kinetochore phospho-docking sites for the hierarchical recruitment of the SAC proteins. Aurora kinase B, MPS1 and budding uninhibited by benzimidazoles 1 (BUB1) also promote sister chromatid biorientation by modulating kinetochore microtubule stability. Moreover, MPS1, BUB1, and PLK1 seem to play key roles in APC/C inhibition by mechanisms dependent and/or independent on MCC assembly. The protein phosphatase 1 and 2A (PP1 and PP2A) are recruited to kinetochores to oppose kinase activity. These phosphatases reverse the phosphorylation of kinetochore targets promoting the microtubule attachment stabilization, sister kinetochore biorientation and SAC silencing. The kinase-phosphatase network is crucial as it renders the SAC a dynamic, graded-signaling, high responsive, and robust process thereby ensuring timely anaphase onset and preventing the generation of proneoplastic aneuploidy.


Subject(s)
M Phase Cell Cycle Checkpoints , Phosphoric Monoester Hydrolases/metabolism , Protein Kinases/metabolism , Animals , Humans , Models, Biological
2.
Cell Death Differ ; 21(1): 15-25, 2014 Jan.
Article in English | MEDLINE | ID: mdl-23787994

ABSTRACT

Conventional anticancer chemotherapy has been historically thought to act through direct killing of tumor cells. This concept stems from the fact that cytotoxic drugs interfere with DNA synthesis and replication. Accumulating evidence, however, indicates that the antitumor activities of chemotherapy also rely on several off-target effects, especially directed to the host immune system, that cooperate for successful tumor eradication. Chemotherapeutic agents stimulate both the innate and adaptive arms of the immune system through several modalities: (i) by promoting specific rearrangements on dying tumor cells, which render them visible to the immune system; (ii) by influencing the homeostasis of the hematopoietic compartment through transient lymphodepletion followed by rebound replenishment of immune cell pools; (iii) by subverting tumor-induced immunosuppressive mechanisms and (iv) by exerting direct or indirect stimulatory effects on immune effectors. Among the indirect ways of immune cell stimulation, some cytotoxic drugs have been shown to induce an immunogenic type of cell death in tumor cells, resulting in the emission of specific signals that trigger phagocytosis of cell debris and promote the maturation of dendritic cells, ultimately resulting in the induction of potent antitumor responses. Here, we provide an extensive overview of the multiple immune-based mechanisms exploited by the most commonly employed cytotoxic drugs, with the final aim of identifying prerequisites for optimal combination with immunotherapy strategies for the development of more effective treatments against cancer.


Subject(s)
Antineoplastic Agents/therapeutic use , Neoplasms/therapy , Adaptive Immunity , Animals , Antineoplastic Agents/toxicity , Cell Death/drug effects , Dendritic Cells/immunology , Dendritic Cells/metabolism , Humans , Immunotherapy , Neoplasms/drug therapy , Neoplasms/immunology , Tumor Microenvironment
3.
Cell Death Differ ; 21(1): 59-68, 2014 Jan.
Article in English | MEDLINE | ID: mdl-23787997

ABSTRACT

The exposure of calreticulin (CRT) on the surface of stressed and dying cancer cells facilitates their uptake by dendritic cells and the subsequent presentation of tumor-associated antigens to T lymphocytes, hence stimulating an anticancer immune response. The chemotherapeutic agent mitoxantrone (MTX) can stimulate the peripheral relocation of CRT in both human and yeast cells, suggesting that the CRT exposure pathway is phylogenetically conserved. Here, we show that pheromones can act as physiological inducers of CRT exposure in yeast cells, thereby facilitating the formation of mating conjugates, and that a large-spectrum inhibitor of G protein-coupled receptors (which resemble the yeast pheromone receptor) prevents CRT exposure in human cancer cells exposed to MTX. An RNA interference screen as well as transcriptome analyses revealed that chemokines, in particular human CXCL8 (best known as interleukin-8) and its mouse ortholog Cxcl2, are involved in the immunogenic translocation of CRT to the outer leaflet of the plasma membrane. MTX stimulated the production of CXCL8 by human cancer cells in vitro and that of Cxcl2 by murine tumors in vivo. The knockdown of CXCL8/Cxcl2 receptors (CXCR1/Cxcr1 and Cxcr2) reduced MTX-induced CRT exposure in both human and murine cancer cells, as well as the capacity of the latter-on exposure to MTX-to elicit an anticancer immune response in vivo. Conversely, the addition of exogenous Cxcl2 increased the immunogenicity of dying cells in a CRT-dependent manner. Altogether, these results identify autocrine and paracrine chemokine signaling circuitries that modulate CRT exposure and the immunogenicity of cell death.


Subject(s)
Calreticulin/metabolism , Interleukin-8/metabolism , Saccharomyces cerevisiae Proteins/metabolism , Animals , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/toxicity , Apoptosis/drug effects , Cell Line, Tumor , Chemokine CXCL2/metabolism , Dendritic Cells/immunology , Dendritic Cells/metabolism , HCT116 Cells , HeLa Cells , Humans , Interleukin-8/antagonists & inhibitors , Interleukin-8/genetics , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mitoxantrone/therapeutic use , Mitoxantrone/toxicity , Neoplasms/drug therapy , Neoplasms/metabolism , Neoplasms/pathology , Receptors, Interleukin-8A/antagonists & inhibitors , Receptors, Interleukin-8A/genetics , Receptors, Interleukin-8A/metabolism , Receptors, Interleukin-8B/antagonists & inhibitors , Receptors, Interleukin-8B/genetics , Receptors, Interleukin-8B/metabolism , Saccharomyces cerevisiae/classification , Saccharomyces cerevisiae/metabolism , Signal Transduction , Transcriptome/drug effects
4.
Cell Death Differ ; 21(1): 69-78, 2014 Jan.
Article in English | MEDLINE | ID: mdl-23811849

ABSTRACT

Immunogenic cell death induced by anticancer chemotherapy is characterized by a series of molecular hallmarks that include the exodus of high-mobility group box 1 protein (HMGB1) from dying cells. HMGB1 is a nuclear nonhistone chromatin-binding protein. It is secreted at the late stages of cellular demise and engages Toll-like receptor4 (TLR4) on dendritic cells (DCs) to accelerate the processing of phagocytic cargo in the DC and to facilitate antigen presentation by DC to T cells. The absence of HMGB1 expression by dying tumor cells exposed to anthracyclines or oxaliplatin compromises DC-dependent T-cell priming by tumor-associated antigens. Here, we show that transplantable tumors exhibiting weak expression of nuclear HMGB1 respond to chemotherapy more effectively if the treatment is combined with the local or systemic administration of a highly purified and physiochemically defined and standardized lipopolysaccharide solution, which acts as a high-potency and exclusive TLR4 agonist, called Dendrophilin (DEN). The synergistic antitumor effects mediated by the combination of chemotherapy and immunotherapy relied upon the presence of the MyD88 (myeloid differentiation primary response gene) adapter of TLR4 (but not that of the TIR-domain-containing adapter-inducing interferon-ß adapter), in line with the well-characterized action of DEN on the MyD88 signaling pathway. DEN and anthracyclines synergized to induce intratumoral accumulation of interferon-γ-producing CD4(+) and CD8(+) T lymphocytes. Moreover, DEN could restore the immunogenicity of dying tumor cells from which HMGB1 had been depleted by RNA interference. These findings underscore the potential clinical utility of combination regimens involving immunogenic chemotherapy and certain TLR4 agonists in advanced HMGB1-deficient cancers.


Subject(s)
Cell Death/drug effects , HMGB1 Protein/metabolism , Lipopolysaccharides/pharmacology , Toll-Like Receptor 4/agonists , Animals , Anthracyclines/therapeutic use , Anthracyclines/toxicity , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/toxicity , Cell Death/immunology , Cell Line, Tumor , Drug Synergism , HMGB1 Protein/antagonists & inhibitors , HMGB1 Protein/genetics , Humans , Immunotherapy , Lipopolysaccharides/therapeutic use , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , RNA, Small Interfering/metabolism , Sarcoma/drug therapy , Sarcoma/mortality , Sarcoma/therapy , Signal Transduction , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Cytotoxic/metabolism , Th1 Cells/immunology , Th1 Cells/metabolism , Toll-Like Receptor 4/metabolism
5.
Vaccine ; 29(18): 3465-75, 2011 Apr 18.
Article in English | MEDLINE | ID: mdl-21382480

ABSTRACT

Virus-like particles (VLPs) are excellent tools for vaccines against pathogens and tumors. They can accommodate foreign polypeptides whose incorporation efficiency and immunogenicity however decrease strongly with the increase of their size. We recently described the CD8(+) T cell immune response against a small foreign antigen (i.e., the 98 amino acid long human papilloma virus E7 protein) incorporated in human immunodeficiency virus (HIV)-1 based VLPs as product of fusion with an HIV-1 Nef mutant (Nef(mut)). Here, we extended our previous investigations by testing the antigenic/immunogenic properties of Nef(mut)-based VLPs incorporating much larger heterologous products, i.e., human hepatitis C virus (HCV) NS3 and influenza virus NP proteins, which are composed of 630 and 498 amino acids, respectively. We observed a remarkable cross-presentation of HCV NS3 in dendritic cells challenged with Nef(mut)-NS3 VLPs, as detected using a NS3 specific CD8(+) T cell clone as well as PBMCs from HCV infected patients. On the other hand, when injected in mice, Nef(mut)-NP VLPs elicited strong anti-NP CD8(+) T cell and CTL immune responses. In addition, we revealed the ability of Nef(mut) incorporated in VLPs to activate and mature primary human immature dendritic cells (iDCs). This phenomenon correlated with the activation of Src tyrosine kinase-related intracellular signaling, and can be transmitted from VLP-challenged to bystander iDCs. Overall, these results prove that Nef(mut)-based VLPs represent a rather flexible platform for the design of innovative CD8(+) T cell vaccines.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Dendritic Cells/immunology , Vaccines, Virus-Like Particle/immunology , Animals , Antigen Presentation , Cross-Priming , HEK293 Cells , HIV-1/immunology , Humans , Immunity, Cellular , Interferon-gamma/immunology , Mice , Mice, Inbred C57BL , Nucleocapsid Proteins , RNA-Binding Proteins/immunology , Viral Core Proteins/immunology , Viral Nonstructural Proteins/immunology , nef Gene Products, Human Immunodeficiency Virus/immunology , src-Family Kinases/immunology
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