Publications by authors named "Giulia Cerrato"

15 Publications

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Cancer cell-autonomous overactivation of PARP1 compromises immunosurveillance in non-small cell lung cancer.

J Immunother Cancer 2022 06;10(6)

Equipe 11 labellisée par la Ligue contre le Cancer, Université de Paris Cité, Sorbonne Université, Centre de Recherche des Cordeliers, INSERM UMR1138, Paris, France

Background: High activity of poly(ADP-ribose) polymerase-1 (PARP1) in non-small cell lung cancer (NSCLC) cells leads to an increase in immunohistochemically detectable PAR, correlating with poor prognosis in patients with NSCLC, as well as reduced tumor infiltration by cytotoxic T lymphocytes (CTLs). Intrigued by this observation, we decided to determine whether PARP1 activity in NSCLC cells may cause an alteration of anticancer immunosurveillance.

Methods: Continuous culture of mouse NSCLC cells in the presence of cisplatin led to the generation of cisplatin-resistant PAR clones. As compared with their parental controls, such PAR cells formed tumors that were less infiltrated by CTLs when they were injected into immunocompetent mice, suggesting a causative link between high PARP1 activity and compromised immunosurveillance. To confirm this cause-and-effect relationship, we used CRISPR/Cas9 technology to knock out PARP1 in two PAR NSCLC mouse cell lines (Lewis lung cancer [LLC] and tissue culture number one [TC1]), showing that the removal of PARP1 indeed restored cisplatin-induced cell death responses.

Results: PARP1 knockout (PARP1) cells became largely resistant to the PARP inhibitor niraparib, meaning that they exhibited less cell death induction, reduced DNA damage response, attenuated metabolic shifts and no induction of PD-L1 and MHC class-I molecules that may affect their immunogenicity. PAR tumors implanted in mice responded to niraparib irrespective of the presence or absence of T lymphocytes, suggesting that cancer cell-autonomous effects of niraparib dominate over its possible immunomodulatory action. While PAR NSCLC mouse cell lines proliferated similarly in immunocompetent and T cell-deficient mice, PARP1 cells were strongly affected by the presence of T cells. PARP1 LLC tumors grew more quickly in immunodeficient than in immunocompetent mice, and PARP1 TC1 cells could only form tumors in T cell-deficient mice, not in immunocompetent controls. Importantly, as compared with PAR controls, the PARP1 LLC tumors exhibited signs of T cell activation in the immune infiltrate such as higher inducible costimulator (ICOS) expression and lower PD-1 expression on CTLs.

Conclusions: These results prove at the genetic level that PARP1 activity within malignant cells modulates the tumor microenvironment.
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http://dx.doi.org/10.1136/jitc-2021-004280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9247697PMC
June 2022

Fine-Tuning Cardiac Insulin-Like Growth Factor 1 Receptor Signaling to Promote Health and Longevity.

Circulation 2022 06 26;145(25):1853-1866. Epub 2022 May 26.

Department of Cardiology (M.A., V.T.-H., A.H., J.V., A.S., P.P.R., D.S., D.v.L. E.B., S.S.), Medical University of Graz, Austria.

Background: The insulin-like growth factor 1 (IGF1) pathway is a key regulator of cellular metabolism and aging. Although its inhibition promotes longevity across species, the effect of attenuated IGF1 signaling on cardiac aging remains controversial.

Methods: We performed a lifelong study to assess cardiac health and lifespan in 2 cardiomyocyte-specific transgenic mouse models with enhanced versus reduced IGF1 receptor (IGF1R) signaling. Male mice with human IGF1R overexpression or dominant negative phosphoinositide 3-kinase mutation were examined at different life stages by echocardiography, invasive hemodynamics, and treadmill coupled to indirect calorimetry. In vitro assays included cardiac histology, mitochondrial respiration, ATP synthesis, autophagic flux, and targeted metabolome profiling, and immunoblots of key IGF1R downstream targets in mouse and human explanted failing and nonfailing hearts, as well.

Results: Young mice with increased IGF1R signaling exhibited superior cardiac function that progressively declined with aging in an accelerated fashion compared with wild-type animals, resulting in heart failure and a reduced lifespan. In contrast, mice with low cardiac IGF1R signaling exhibited inferior cardiac function early in life, but superior cardiac performance during aging, and increased maximum lifespan, as well. Mechanistically, the late-life detrimental effects of IGF1R activation correlated with suppressed autophagic flux and impaired oxidative phosphorylation in the heart. Low IGF1R activity consistently improved myocardial bioenergetics and function of the aging heart in an autophagy-dependent manner. In humans, failing hearts, but not those with compensated hypertrophy, displayed exaggerated IGF1R expression and signaling activity.

Conclusions: Our findings indicate that the relationship between IGF1R signaling and cardiac health is not linear, but rather biphasic. Hence, pharmacological inhibitors of the IGF1 pathway, albeit unsuitable for young individuals, might be worth considering in older adults.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.122.059863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9203038PMC
June 2022

Local anesthetics elicit immune-dependent anticancer effects.

J Immunother Cancer 2022 04;10(4)

Equipe labellisée par la Ligue contre le cancer, Université de Paris Cité, Sorbonne Université, INSERM UMR1138, Centre de Recherche des Cordeliers, Paris, France

Background: Retrospective clinical trials reported a reduced local relapse rate, as well as improved overall survival after injection of local anesthetics during cancer surgery. Here, we investigated the anticancer effects of six local anesthetics used in clinical practice.

Results: , local anesthetics induced signs of cancer cell stress including inhibition of oxidative phosphorylation, and induction of autophagy as well as endoplasmic reticulum (ER) stress characterized by the splicing of X-box binding protein 1 (XBP1s) mRNA, cleavage of activating transcription factor 6 (ATF6), phosphorylation of eIF2α and subsequent upregulation of activating transcription factor 4 (ATF4). Both eIF2α phosphorylation and autophagy required the ER stress-relevant eukaryotic translation initiation factor 2 alpha kinase 3 (EIF2AK3, best known as PERK). Local anesthetics also activated two hallmarks of immunogenic cell death, namely, the release of ATP and high-mobility group box 1 protein (HMGB1), yet failed to cause the translocation of calreticulin (CALR) from the ER to the plasma membrane. , locally injected anesthetics decreased tumor growth and improved survival in several models of tumors established in immunocompetent mice. Systemic immunotherapy with PD-1 blockade or intratumoral injection of recombinant CALR protein, increased the antitumor effects of local anesthetics. Local anesthetics failed to induce antitumor effects in immunodeficient mice or against cancers unable to activate ER stress or autophagy due to the knockout of EIF2AK3/PERK or ATG5, respectively. Uncoupling agents that inhibit oxidative phosphorylation and induce autophagy and ER stress mimicked the immune-dependent antitumor effects of local anesthetics.

Conclusion: Altogether, these results indicate that local anesthetics induce a therapeutically relevant pattern of immunogenic stress responses in cancer cells.
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http://dx.doi.org/10.1136/jitc-2021-004151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9052055PMC
April 2022

Biological Investigation of a Water-Soluble Isoginkgetin-Phosphate Analogue, Targeting the Spliceosome with Antitumor Activity.

J Med Chem 2022 03 2;65(6):4633-4648. Epub 2022 Mar 2.

Université Paris-Saclay, Institut Gustave Roussy, Inserm, Immunologie des tumeurs et Immunothérapie, Villejuif 94805, France.

The first total synthesis of the natural product Isoginkgetin as well as four water-soluble Isoginkgetin-phosphate analogues is reported herein. Moreover, the full study of the phosphate analogue with respect to pharmacological properties (metabolic and plasmatic stabilities, pharmacokinetic, off-target, etc.) as well as and biological activities are disclosed herein.
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http://dx.doi.org/10.1021/acs.jmedchem.1c01654DOI Listing
March 2022

High throughput screening for autophagy.

Methods Cell Biol 2021 23;165:89-101. Epub 2021 Jan 23.

Centre de Recherche des Cordeliers, Équipe 11 Labellisée par la Ligue Contre le Cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France; Université Paris Sud, Paris Saclay, Faculty of Medicine, Kremlin-Bicêtre, France. Electronic address:

Robotized high throughput screening allows for the assessment of autophagy in a large number of samples. Here, we describe a drug discovery platform for the phenotypic identification of novel autophagy inducers by means of automated cell biology workflows employing robotized cell culture, sample preparation and data acquisition. In this setting, fluorescent biosensor cells that express microtubule-associated proteins 1A/1B light chain 3B (best known as LC3) conjugated to green fluorescent protein (GFP), are utilized together with automated high content microscopy for the image-based assessment of autophagy. In sum, we detail a drug discovery screening workflow from high throughput sample preparation and processing to data acquisition and analysis.
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http://dx.doi.org/10.1016/bs.mcb.2020.12.011DOI Listing
November 2021

Live cell imaging of LC3 dynamics.

Methods Cell Biol 2021 1;164:27-38. Epub 2021 Mar 1.

Centre de Recherche des Cordeliers, Équipe 11 Labellisée par la Ligue Contre le Cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Université Paris Saclay, Villejuif, France; Pôle de Biologie, Hôpital Européen Georges-Pompidou, AP-HP, Paris, France; Suzhou Institute for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, China; Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. Electronic address:

Macroautophagy (hereafter referred to as autophagy) serves the liberation of energy resources through the degradation of cellular components and is characterized by the formation of double-membraned vesicles, commonly referred to as autophagosomes. Microtubule-associated proteins 1A/1B light chain 3B (hereafter referred to as LC3) plays a crucial role during autophagosome formation, as cleavage of its immature form and subsequent conjugation to phosphatidylethanolamine facilitates autophagosomal membrane biogenesis. Indeed, the redistribution of green fluorescent protein (GFP)-conjugated LC3 from a diffuse cytosolic pattern into forming autophagosomes constitutes a morphological phenotype (commonly referred to as LC3 puncta) applicable to phenotypic analysis. The quantification of LC3 puncta in end-point assays has extensively been used in the past, allowing for the identification of autophagy modulators. Here, we describe a robust method employing automated confocal live cell imaging for the study of time-resolved LC3 dynamics. Furthermore, this method can be used to differentiate between phenotypes such as the homogeneous distribution of LC3 puncta in the cytoplasm, and the aggregation of LC3 clusters juxtaposed to the nucleus thus allowing for functional predictions.
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http://dx.doi.org/10.1016/bs.mcb.2020.10.003DOI Listing
November 2021

High-throughput label-free detection of DNA-to-RNA transcription inhibition using brightfield microscopy and deep neural networks.

Comput Biol Med 2021 06 4;133:104371. Epub 2021 Apr 4.

Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le Cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Villejuif, France; Suzhou Institute for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, China; Po^le de Biologie, Ho^pital Européen Georges Pompidou, AP-HP, Paris, France; Karolinska Institutet, Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden.

Drug discovery is in constant evolution and major advances have led to the development of in vitro high-throughput technologies, facilitating the rapid assessment of cellular phenotypes. One such phenotype is immunogenic cell death, which occurs partly as a consequence of inhibited RNA synthesis. Automated cell-imaging offers the possibility of combining high-throughput with high-content data acquisition through the simultaneous computation of a multitude of cellular features. Usually, such features are extracted from fluorescence images, hence requiring labeling of the cells using dyes with possible cytotoxic and phototoxic side effects. Recently, deep learning approaches have allowed the analysis of images obtained by brightfield microscopy, a technique that was for long underexploited, with the great advantage of avoiding any major interference with cellular physiology or stimulatory compounds. Here, we describe a label-free image-based high-throughput workflow that accurately detects the inhibition of DNA-to-RNA transcription. This is achieved by combining two successive deep convolutional neural networks, allowing (1) to automatically detect cellular nuclei (thus enabling monitoring of cell death) and (2) to classify the extracted nuclear images in a binary fashion. This analytical pipeline is R-based and can be easily applied to any microscopic platform.
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http://dx.doi.org/10.1016/j.compbiomed.2021.104371DOI Listing
June 2021

Oleate-induced aggregation of LC3 at the trans-Golgi network is linked to a protein trafficking blockade.

Cell Death Differ 2021 05 17;28(5):1733-1752. Epub 2020 Dec 17.

Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, INSERM UMR1138, Centre de Recherche des Cordeliers, Paris, France.

Oleate, the most abundant endogenous and dietary cis-unsaturated fatty acid, has the atypical property to cause the redistribution of microtubule-associated proteins 1A/1B light chain 3B (referred to as LC3) to the trans-Golgi network (TGN), as shown here. A genome-wide screen identified multiple, mostly Golgi transport-related genes specifically involved in the oleate-induced relocation of LC3 to the Golgi apparatus. Follow-up analyses revealed that oleate also caused the retention of secreted proteins in the TGN, as determined in two assays in which the secretion of proteins was synchronized, (i) an assay involving a thermosensitive vesicular stomatitis virus G (VSVG) protein that is retained in the endoplasmic reticulum (ER) until the temperature is lowered, and (ii) an isothermic assay involving the reversible retention of the protein of interest in the ER lumen and that was used both in vitro and in vivo. A pharmacological screen searching for agents that induce LC3 aggregation at the Golgi apparatus led to the identification of "oleate mimetics" that share the capacity to block conventional protein secretion. In conclusion, oleate represents a class of molecules that act on the Golgi apparatus to cause the recruitment of LC3 and to stall protein secretion.
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http://dx.doi.org/10.1038/s41418-020-00699-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8167183PMC
May 2021

A genome-wide RNA interference screen disentangles the Golgi tropism of LC3.

Autophagy 2021 03 23;17(3):820-822. Epub 2020 Dec 23.

Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, INSERM UMR1138, Centre de Recherche des Cordeliers, Paris, France.

Oleate, the most abundantly occurring -unsaturated fatty acid, has the particularity to induce the accumulation of MAP1LC3B/LC3 (microtubule associated protein 1 light chain 3 beta) at the -Golgi apparatus. A genome-wide RNA interference screen designed to identify the mechanisms of this LC3 redistribution led to the identification of a BECN1-PIK3C3-independent pathway that, however, requires the ATG12-ATG5 and ATG7-dependent conjugation system, and several genes/proteins involved in endoplasmic reticulum (ER)-to-Golgi anterograde protein transport, as well as the unfolded protein response, including the integrated stress response that results in the phosphorylation of EIF2A/eIF2α (eukaryotic translation initiation factor 2A). Functional experiments revealed that oleate blocks conventional protein secretion, stalling the process at the level of the -Golgi network. Oleate-induced blockade of protein secretion occurred even after depletion of ATG5, suggesting that it does not rely on the recruitment of LC3 to the Golgi apparatus (which does require ATG5). Rather, it appears that oleate and other pharmacological inhibitors of protein secretion with a similar mode of action provoke a perturbation of the -Golgi compartment that secondarily results in the local enrichment of LC3.
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http://dx.doi.org/10.1080/15548627.2020.1861836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032232PMC
March 2021

A TLR3 Ligand Reestablishes Chemotherapeutic Responses in the Context of FPR1 Deficiency.

Cancer Discov 2021 02 12;11(2):408-423. Epub 2020 Oct 12.

Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, Paris, France.

For anthracycline-based chemotherapy to be immunogenic, dying cancer cells must release annexin A1 (ANXA1) that subsequently interacts with the pattern recognition receptor, formyl peptide receptor 1 (FPR1), on the surface of dendritic cells (DC). Approximately 30% of individuals bear loss-of-function alleles of , calling for strategies to ameliorate their anticancer immune response. Here, we show that immunotherapy with a ligand of Toll-like receptor-3, polyinosinic:polycytidylic acid (pIC), restores the deficient response to chemotherapy of tumors lacking ANXA1 developing in immunocompetent mice or those of normal cancers growing in FPR1-deficient mice. This effect was accompanied by improved DC- and T-lymphocyte-mediated anticancer immunity. Of note, carcinogen-induced breast cancers precociously developed in FPR1-deficient mice as compared with wild-type controls. A similar tendency for earlier cancer development was found in patients carrying the loss-of-function allele of . These findings have potential implications for the clinical management of FPR1-deficient patients. SIGNIFICANCE: The loss-of-function variant rs867228 in , harbored by approximately 30% of the world population, is associated with the precocious manifestation of breast, colorectal, esophageal, and head and neck carcinomas. pIC restores deficient chemotherapeutic responses in mice lacking , suggesting a personalized strategy for compensating for the FPR1 defect..
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http://dx.doi.org/10.1158/2159-8290.CD-20-0465DOI Listing
February 2021

Phosphorylation of eukaryotic initiation factor-2α (eIF2α) in autophagy.

Cell Death Dis 2020 06 8;11(6):433. Epub 2020 Jun 8.

Equipe Labellisée par la Ligue Contre le Cancer, Université de Paris, Sorbonne Université, INSERM UMR1138, Centre de Recherche des Cordeliers, Paris, France.

The integrated stress response is characterized by the phosphorylation of eukaryotic initiation factor-2α (eIF2α) on serine 51 by one out of four specific kinases (EIF2AK1 to 4). Here we provide three series of evidence suggesting that macroautophagy (to which we refer to as autophagy) induced by a variety of distinct pharmacological agents generally requires this phosphorylation event. First, the induction of autophagic puncta by various distinct compounds was accompanied by eIF2α phosphorylation on serine 51. Second, the modulation of autophagy by >30 chemically unrelated agents was partially inhibited in cells expressing a non-phosphorylable (S51A) mutant of eIF2α or lacking all four eIF2α kinases, although distinct kinases were involved in the response to different autophagy inducers. Third, inhibition of eIF2α phosphatases was sufficient to stimulate autophagy. In synthesis, it appears that eIF2α phosphorylation is a central event for the stimulation of autophagy.
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http://dx.doi.org/10.1038/s41419-020-2642-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280501PMC
June 2020

Inhibition of transcription by dactinomycin reveals a new characteristic of immunogenic cell stress.

EMBO Mol Med 2020 05 23;12(5):e11622. Epub 2020 Apr 23.

Equipe labellisée par la Ligue contre le Cancer, Sorbonne Université, INSERM UMR1138, Centre de Recherche des Cordeliers, Université de Paris, Paris, France.

Chemotherapy still constitutes the standard of care for the treatment of most neoplastic diseases. Certain chemotherapeutics from the oncological armamentarium are able to trigger pre-mortem stress signals that lead to immunogenic cell death (ICD), thus inducing an antitumor immune response and mediating long-term tumor growth reduction. Here, we used an established model, built on artificial intelligence to identify, among a library of 50,000 compounds, anticancer agents that, based on their molecular descriptors, were predicted to induce ICD. This algorithm led us to the identification of dactinomycin (DACT, best known as actinomycin D), a highly potent cytotoxicant and ICD inducer that mediates immune-dependent anticancer effects in vivo. Since DACT is commonly used as an inhibitor of DNA to RNA transcription, we investigated whether other experimentally established or algorithm-selected, clinically employed ICD inducers would share this characteristic. As a common leitmotif, a panel of pharmacological ICD stimulators inhibited transcription and secondarily translation. These results establish the inhibition of RNA synthesis as an initial event for ICD induction.
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http://dx.doi.org/10.15252/emmm.201911622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7207166PMC
May 2020

Quantitative determination of phagocytosis by bone marrow-derived dendritic cells via imaging flow cytometry.

Methods Enzymol 2020 2;632:27-37. Epub 2019 Aug 2.

Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France; INSERM, U1138, Paris, France; Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France; Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France; Université Pierre et Marie Curie/Paris VI, Paris, France; Faculté de Medicine, Université Paris Saclay/Paris XI, Le Kremlin-Bicêtre, France; Suzhou Institute for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, China; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France; Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden. Electronic address:

Immunogenic cell death (ICD), induced by certain anticancer chemotherapeutics, leads to the emission of danger associated molecular patterns (DAMP) by cancer cells, which facilitates the attraction, activation and maturation of dendritic cells (DC) as well as the subsequent priming of effector T cells. In this context calreticulin (CALR) exposed at an early stage of ICD at the surface of the cancer cells serves as phagocytic signal and triggers the formation of immunological synapses between malignant cells and DC. Subsequent phagocytosis facilitates the transfer of tumor associated antigen and thus depicts a fundamental step in the generation of anticancer immunity. Here we provide an imaging flowcytometric protocol for the quantification of ICD-associated DC phagocytosis of cancer cells. As compared to the traditional flowcytometry-based analysis, the presented method offers additional means of differentiation between the transient formation of immunological synapses and the final DC-mediated phagocytosis of cancer cells.
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http://dx.doi.org/10.1016/bs.mie.2019.07.021DOI Listing
December 2020

Trial watch: Peptide-based vaccines in anticancer therapy.

Oncoimmunology 2018;7(12):e1511506. Epub 2018 Sep 6.

Université Paris Descartes/Paris V, Paris, France.

Peptide-based anticancer vaccination aims at stimulating an immune response against one or multiple tumor-associated antigens (TAAs) following immunization with purified, recombinant or synthetically engineered epitopes. Despite high expectations, the peptide-based vaccines that have been explored in the clinic so far had limited therapeutic activity, largely due to cancer cell-intrinsic alterations that minimize antigenicity and/or changes in the tumor microenvironment that foster immunosuppression. Several strategies have been developed to overcome such limitations, including the use of immunostimulatory adjuvants, the co-treatment with cytotoxic anticancer therapies that enable the coordinated release of damage-associated molecular patterns, and the concomitant blockade of immune checkpoints. Personalized peptide-based vaccines are also being explored for therapeutic activity in the clinic. Here, we review recent preclinical and clinical progress in the use of peptide-based vaccines as anticancer therapeutics. CMP: carbohydrate-mimetic peptide; CMV: cytomegalovirus; DC: dendritic cell; FDA: Food and Drug Administration; HPV: human papillomavirus; MDS: myelodysplastic syndrome; MHP: melanoma helper vaccine; NSCLC: non-small cell lung carcinoma; ODD: orphan drug designation; PPV: personalized peptide vaccination; SLP: synthetic long peptide; TAA: tumor-associated antigen; TNA: tumor neoantigen.
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http://dx.doi.org/10.1080/2162402X.2018.1511506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279318PMC
September 2018

Trans-Fats Inhibit Autophagy Induced by Saturated Fatty Acids.

EBioMedicine 2018 Apr 27;30:261-272. Epub 2018 Mar 27.

Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Equipe 11 labellisée Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France; Institut National de la Santé et de la Recherche Médicale, U1138 Paris, France; Université Pierre et Marie Curie, Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France; Faculty of Medicine, University of Paris Sud, Kremlin-Bicêtre, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France; Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden. Electronic address:

Depending on the length of their carbon backbone and their saturation status, natural fatty acids have rather distinct biological effects. Thus, longevity of model organisms is increased by extra supply of the most abundant natural cis-unsaturated fatty acid, oleic acid, but not by that of the most abundant saturated fatty acid, palmitic acid. Here, we systematically compared the capacity of different saturated, cis-unsaturated and alien (industrial or ruminant) trans-unsaturated fatty acids to provoke cellular stress in vitro, on cultured human cells expressing a battery of distinct biosensors that detect signs of autophagy, Golgi stress and the unfolded protein response. In contrast to cis-unsaturated fatty acids, trans-unsaturated fatty acids failed to stimulate signs of autophagy including the formation of GFP-LC3B-positive puncta, production of phosphatidylinositol-3-phosphate, and activation of the transcription factor TFEB. When combined effects were assessed, several trans-unsaturated fatty acids including elaidic acid (the trans-isomer of oleate), linoelaidic acid, trans-vaccenic acid and palmitelaidic acid, were highly efficient in suppressing autophagy and endoplasmic reticulum stress induced by palmitic, but not by oleic acid. Elaidic acid also inhibited autophagy induction by palmitic acid in vivo, in mouse livers and hearts. We conclude that the well-established, though mechanistically enigmatic toxicity of trans-unsaturated fatty acids may reside in their capacity to abolish cytoprotective stress responses induced by saturated fatty acids.
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http://dx.doi.org/10.1016/j.ebiom.2018.03.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5952403PMC
April 2018
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