Publications by authors named "Guido Kroemer"

1,154 Publications

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PARP1 inhibition elicits immune responses against non-small cell lung cancer.

Oncoimmunology 2022 11;11(1):2111915. Epub 2022 Aug 11.

Equipe 11 Labellisée Par la Ligue Contre le Cancer, Université de Paris Cité, Sorbonne Université, Paris, France.

High levels of intracellular poly(ADP-ribose) (PAR) resulting from an elevated activity of PAR polymerase-1 (PARP1) correlate with poor infiltration of non-small cell lung cancers by cytotoxic T lymphocytes and dismal patient prognosis. Preclinical experimentation now demonstrates that PARP1 inhibition in cancer cells mediates strong immunostimulatory effects.
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http://dx.doi.org/10.1080/2162402X.2022.2111915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9377245PMC
August 2022

AIF Overexpression Aggravates Oxidative Stress in Neonatal Male Mice After Hypoxia-Ischemia Injury.

Mol Neurobiol 2022 Aug 17. Epub 2022 Aug 17.

Henan Key Laboratory of Child Brain Injury, Institute of Neuroscience and Third Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, China.

There are sex differences in the severity, mechanisms, and outcomes of neonatal hypoxia-ischemia (HI) brain injury, and apoptosis-inducing factor (AIF) may play a critical role in this discrepancy. Based on previous findings that AIF overexpression aggravates neonatal HI brain injury, we further investigated potential sex differences in the severity and molecular mechanisms underlying the injury using mice that overexpress AIF from homozygous transgenes. We found that the male sex significantly aggravated AIF-driven brain damage, as indicated by the injury volume in the gray matter (2.25 times greater in males) and by the lost volume of subcortical white matter (1.71 greater in males) after HI. As compared to females, male mice exhibited more severe brain injury, correlating with reduced antioxidant capacities, more pronounced protein carbonylation and nitration, and increased neuronal cell death. Under physiological conditions (without HI), the doublecortin-positive area in the dentate gyrus of females was 1.15 times larger than in males, indicating that AIF upregulation effectively promoted neurogenesis in females in the long term. We also found that AIF stimulated carbohydrate metabolism in young males. Altogether, these findings corroborate earlier studies and further demonstrate that AIF is involved in oxidative stress, which contributes to the sex-specific differences observed in neonatal HI brain injury.
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http://dx.doi.org/10.1007/s12035-022-02987-0DOI Listing
August 2022

Escherichia coli-specific CXCL13-producing TFH are associated with clinical efficacy of neoadjuvant PD-1 blockade against muscle-invasive bladder cancer.

Cancer Discov 2022 Aug 5. Epub 2022 Aug 5.

Institut Gustave Roussy, Villejuif, France.

Biomarkers guiding the neoadjuvant use of immune checkpoint inhibitors (ICBs) are needed for patients with localized muscle invasive bladder cancers (MIBC). Profiling tumor and blood samples, we found that follicular helper CD4+ T cells (TFH) are among the best therapeutic targets of pembrolizumab correlating with progression-free survival. TFH were associated with tumoral CD8 and PD-L1 expression at baseline, and the induction of tertiary lymphoid structures post-pembrolizumab. Blood central memory TFH accumulated in tumors where they produce CXCL13, a chemokine found in the plasma of responders only. IgG4+CD38+ TFH residing in bladder tissues correlated with clinical benefit. Finally, TFH and IgG directed against urothelium invasive Escherichia coli dictated clinical responses to pembrolizumab in three independent cohorts. The links between tumor infection and success of ICB immunomodulation should be prospectively assessed at a larger scale.
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http://dx.doi.org/10.1158/2159-8290.CD-22-0201DOI Listing
August 2022

Keeping Cell Death Alive: An Introduction into the French Cell Death Research Network.

Biomolecules 2022 06 28;12(7). Epub 2022 Jun 28.

INSERM U1218, Institut Bergonié, 33000 Bordeaux, France.

Since the Nobel Prize award more than twenty years ago for discovering the core apoptotic pathway in , apoptosis and various other forms of regulated cell death have been thoroughly characterized by researchers around the world. Although many aspects of regulated cell death still remain to be elucidated in specific cell subtypes and disease conditions, many predicted that research into cell death was inexorably reaching a plateau. However, this was not the case since the last decade saw a multitude of cell death modalities being described, while harnessing their therapeutic potential reached clinical use in certain cases. In line with keeping research into cell death alive, francophone researchers from several institutions in France and Belgium established the French Cell Death Research Network (FCDRN). The research conducted by FCDRN is at the leading edge of emerging topics such as non-apoptotic functions of apoptotic effectors, paracrine effects of cell death, novel canonical and non-canonical mechanisms to induce apoptosis in cell death-resistant cancer cells or regulated forms of necrosis and the associated immunogenic response. Collectively, these various lines of research all emerged from the study of apoptosis and in the next few years will increase the mechanistic knowledge into regulated cell death and how to harness it for therapy.
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http://dx.doi.org/10.3390/biom12070901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9313292PMC
June 2022

Balancing energy and protein homeostasis at ER-mitochondria contact sites.

Sci Signal 2022 07 5;15(741):eabm7524. Epub 2022 Jul 5.

Center for Geroscience, Brain Health, and Metabolism, 70086 Santiago, Chile.

The endoplasmic reticulum (ER) is the largest organelle of the cell and participates in multiple essential functions, including the production of secretory proteins, lipid synthesis, and calcium storage. Sustaining proteostasis requires an intimate coupling with energy production. Mitochondrial respiration evolved to be functionally connected to ER physiology through a physical interface between both organelles known as mitochondria-associated membranes. This quasi-synaptic structure acts as a signaling hub that tunes the function of both organelles in a bidirectional manner and controls proteostasis, cell death pathways, and mitochondrial bioenergetics. Here, we discuss the main signaling mechanisms governing interorganellar communication and their putative role in diseases including cancer and neurodegeneration.
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http://dx.doi.org/10.1126/scisignal.abm7524DOI Listing
July 2022

A nanoparticle-based tour de force for enhancing immunogenic cell death elicited by photodynamic therapy.

Oncoimmunology 2022 8;11(1):2098658. Epub 2022 Jul 8.

Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Université Paris Saclay, Villejuif, France.

Immunogenic cell death (ICD) involves the release of ATP, which can be destroyed by ectonucleotidases, converting it into immunosuppressive adenosine. Hence, inhibition of such ectonucleotidases is a strategy for enhancing ICD-elicited anticancer immunity. In a recent paper in Science Translational Medicine, Mao et al. report the construction of reactive oxygen-labile nanoparticles that bear two functionalities, namely (i) the capacity to sensitize cancer cells to near-infrared light (NIL) irradiation, hence inducing ICD in the context of photodynamic therapy, and (ii) the peculiarity to respond to NIL by releasing a pharmacological inhibitor of ectonucleotidases, hence enhancing intratumoral concentrations of ATP. In preclinical models, these nanoparticles are highly efficient in inducing anticancer immune responses.
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http://dx.doi.org/10.1080/2162402X.2022.2098658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9272828PMC
July 2022

Dendritic cell transfer for cancer immunotherapy.

Int Rev Cell Mol Biol 2022 29;370:33-64. Epub 2022 Jun 29.

Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Université Paris Saclay, Villejuif, France; 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. Electronic address:

Dendritic cells (DCs) play a major role in cancer immunosurveillance as they bridge innate and adaptive immunity by detecting tumor-associated antigens and presenting them to T lymphocytes. The adoptive transfer of antigen loaded DCs has been proposed as an immunotherapeutic approach for the treatment of various types of cancer. Nevertheless, despite promising preclinical data, the therapeutic efficacy of DC transfer is still deceptive in cancer patients. Here we summarize recent findings in DC biology with a special focus on the development of actionable therapeutic strategies and discuss experimental and clinical approaches that aim at improving the efficacy of DC-based immunotherapies, including, but not limited to, optimized DC production and antigen loading, stimulated maturation, the co-treatment with additional immunotherapies, as well as the inhibition of DC checkpoints.
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http://dx.doi.org/10.1016/bs.ircmb.2022.03.003DOI Listing
June 2022

Spermidine overrides INSR (insulin receptor)-IGF1R (insulin-like growth factor 1 receptor)-mediated inhibition of autophagy in the aging heart.

Autophagy 2022 Jul 10:1-3. Epub 2022 Jul 10.

Department of Cardiology, Medical University of Graz, Graz, Austria.

Although attenuated IGF1R (insulin-like growth factor 1 receptor) signaling has long been viewed to promote longevity in model organisms, adverse effects on the heart have been the subject of major concern. We observed that IGF1R is overexpressed in cardiac tissues from patients with end-stage non-ischemic heart failure, coupled to the activation of the IGF1R downstream effector AKT/protein kinase B and inhibition of ULK1 (unc-51 like autophagy activating kinase 1). Transgenic overexpression of human IGF1R in cardiomyocytes from mice initially induces physiological cardiac hypertrophy and superior function, but later in life confers a negative impact on cardiac health, causing macroautophagy/autophagy inhibition as well as impaired oxidative phosphorylation, thus reducing life expectancy. Treatment with the autophagy inducer and caloric restriction mimetic spermidine ameliorates most of these IGF1R-induced cardiotoxic effects in vivo. Moreover, inhibition of IGF1R signaling by means of a dominant-negative phosphoinositide 3-kinase (PI3K) mutant induces cardioprotective autophagy, restores myocardial bioenergetics and improves late-life survival. Hence, our results demonstrate that IGF1R exerts a dual biphasic impact on cardiac health, and that autophagy mediates the late-life geroprotective effects of IGF1R inhibition in the heart.
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http://dx.doi.org/10.1080/15548627.2022.2095835DOI Listing
July 2022

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

PD-1 blockade synergizes with oxaliplatin-based, but not cisplatin-based, chemotherapy of gastric cancer.

Oncoimmunology 2022 24;11(1):2093518. Epub 2022 Jun 24.

Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Université Paris Saclay, Villejuif, France.

Preclinical experimentation revealed that established cancers treated with the immunogenic cell death (ICD) inducer oxaliplatin are sensitized to immune checkpoint inhibitors targeting PD-1. In contrast, no such sensitizing effect is observed when cisplatin, a non-immunogenic cell death inducer is used. Two randomized phase III clinical trials targeting unresectable gastric and gastro-esophageal junction carcinomas apparently validate this observation. Thus, oxaliplatin-based chemotherapy (together with capecitabine or 5-fluorouracil plus leucovorin) favorably interacted with nivolumab, yielding improved outcome. In contrast, the outcome of cisplatin-based chemotherapy (together with capecitabine or 5-fluorouracil) failed to be improved by concomitant treatment with pembrolizumab. These clinical findings underscore the importance of choosing appropriate ICD-inducing cytotoxicants for the development of chemoimmunotherapeutic regimens. Unfortunately, the FDA and EMA have approved PD-1 blockade in combination with "platinum-based chemotherapy" without specifying the precise nature of the platinum-containing drug. This is a non sequitur. Based on the available clinical data, such approvals should be restricted to the use of oxaliplatin.
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http://dx.doi.org/10.1080/2162402X.2022.2093518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9235886PMC
June 2022

The endoplasmic reticulum chaperone BiP: a target for immunogenic cell death inducers?

Oncoimmunology 2022 21;11(1):2092328. Epub 2022 Jun 21.

Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Université Paris Saclay, Villejuif, France.

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http://dx.doi.org/10.1080/2162402X.2022.2092328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9225301PMC
June 2022

Metabolic Profiling of CHO Cells during the Production of Biotherapeutics.

Cells 2022 06 15;11(12). Epub 2022 Jun 15.

Sanofi R&D, 94400 Vitry-sur-Seine, France.

As indicated by an ever-increasing number of FDA approvals, biotherapeutics constitute powerful tools for the treatment of various diseases, with monoclonal antibodies (mAbs) accounting for more than 50% of newly approved drugs between 2014 and 2018 (Walsh, 2018). The pharmaceutical industry has made great progress in developing reliable and efficient bioproduction processes to meet the demand for recombinant mAbs. Mammalian cell lines are preferred for the production of functional, complex recombinant proteins including mAbs, with Chinese hamster ovary (CHO) cells being used in most instances. Despite significant advances in cell growth control for biologics manufacturing, cellular responses to environmental changes need to be understood in order to further improve productivity. Metabolomics offers a promising approach for developing suitable strategies to unlock the full potential of cellular production. This review summarizes key findings on catabolism and anabolism for each phase of cell growth (exponential growth, the stationary phase and decline) with a focus on the principal metabolic pathways (glycolysis, the pentose phosphate pathway and the tricarboxylic acid cycle) and the families of biomolecules that impact these circuities (nucleotides, amino acids, lipids and energy-rich metabolites).
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http://dx.doi.org/10.3390/cells11121929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9221972PMC
June 2022

NAD and Vascular Dysfunction: From Mechanisms to Therapeutic Opportunities.

J Lipid Atheroscler 2022 May 6;11(2):111-132. Epub 2022 Apr 6.

Department of Cardiology, Medical University of Graz, Graz, Austria.

Nicotinamide adenine dinucleotide (NAD) is an essential and pleiotropic coenzyme involved not only in cellular energy metabolism, but also in cell signaling, epigenetic regulation, and post-translational protein modifications. Vascular disease risk factors are associated with aberrant NAD metabolism. Conversely, the therapeutic increase of NAD levels through the administration of NAD precursors or inhibitors of NAD-consuming enzymes reduces chronic low-grade inflammation, reactivates autophagy and mitochondrial biogenesis, and enhances oxidative metabolism in vascular cells of humans and rodents with vascular pathologies. As such, NAD has emerged as a potential target for combatting age-related cardiovascular and cerebrovascular disorders. This review discusses NAD-regulated mechanisms critical for vascular health and summarizes new advances in NAD research directly related to vascular aging and disease, including hypertension, atherosclerosis, coronary artery disease, and aortic aneurysms. Finally, we enumerate challenges and opportunities for NAD repletion therapy while anticipating the future of this exciting research field, which will have a major impact on vascular medicine.
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http://dx.doi.org/10.12997/jla.2022.11.2.111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9133775PMC
May 2022

Trial Watch: combination of tyrosine kinase inhibitors (TKIs) and immunotherapy.

Oncoimmunology 2022 26;11(1):2077898. Epub 2022 May 26.

Team "Metabolism, Cancer & Immunity", Centre de Recherche des Cordeliers, INSERM UMRS1138, Université Paris Cité, Sorbonne Université, Paris, France.

The past decades witnessed the clinical employment of targeted therapies including but not limited to tyrosine kinase inhibitors (TKIs) that restrain a broad variety of pro-tumorigenic signals. TKIs can be categorized into (i) agents that directly target cancer cells, (ii) normalize angiogenesis or (iii) affect cells of the hematologic lineage. However, a clear distinction of TKIs based on this definition is limited by the fact that many TKIs designed to inhibit cancer cells have also effects on immune cells that are being discovered. Additionally, TKIs originally designed to target hematological cancers exhibit bioactivities on healthy cells of the same hematological lineage. TKIs have been described to improve immune recognition and cancer immunosurveillance, providing the scientific basis to combine TKIs with immunotherapy. Indeed, combination of TKIs with immunotherapy showed synergistic effects in preclinical models and clinical trials and some combinations of TKIs normalizing angiogenesis with immune checkpoint blocking antibodies have already been approved by the FDA for cancer therapy. However, the identification of appropriate drug combinations as well as optimal dosing and scheduling needs to be improved in order to obtain tangible progress in cancer care. This Trial Watch summarizes active clinical trials combining TKIs with various immunotherapeutic strategies to treat cancer patients.
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http://dx.doi.org/10.1080/2162402X.2022.2077898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9154809PMC
May 2022

Boosting the immunotherapy response by nutritional interventions.

J Clin Invest 2022 06;132(11)

Equipe Labellisée par la Ligue Contre le Cancer, Université de Paris Cité, Sorbonne Université, Institut Universitaire de France, Inserm U1138, Centre de Recherche des Cordeliers, Paris, France.

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http://dx.doi.org/10.1172/JCI161483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9151683PMC
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

Immunogenic stress induced by local anesthetics injected into neoplastic lesions.

Oncoimmunology 2022 16;11(1):2077897. Epub 2022 May 16.

Equipe Labellisée Par La Ligue Contre Le Cancer, Université de Paris, Sorbonne Université, INSERM UMR1138, Centre de Recherche des Cordeliers, Institut Universitaire de France, Paris, France.

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http://dx.doi.org/10.1080/2162402X.2022.2077897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9116388PMC
May 2022

Doxorubicin impacts chromatin binding of HMGB1, Histone H1 and retinoic acid receptor.

Sci Rep 2022 05 16;12(1):8087. Epub 2022 May 16.

Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.

Doxorubicin (Dox), a widely used anticancer DNA-binding drug, affects chromatin in multiple ways, and these effects contribute to both its efficacy and its dose-limiting side effects, especially cardiotoxicity. Here, we studied the effects of Dox on the chromatin binding of the architectural proteins high mobility group B1 (HMGB1) and the linker histone H1, and the transcription factor retinoic acid receptor (RARα) by fluorescence recovery after photobleaching (FRAP) and fluorescence correlation spectroscopy (FCS) in live cells. At lower doses, Dox increased the binding of HMGB1 to DNA while decreasing the binding of the linker histone H1. At higher doses that correspond to the peak plasma concentrations achieved during chemotherapy, Dox reduced the binding of HMGB1 as well. This biphasic effect is interpreted in terms of a hierarchy of competition between the ligands involved and Dox-induced local conformational changes of nucleosome-free DNA. Combined, FRAP and FCS mobility data suggest that Dox decreases the overall binding of RARα to DNA, an effect that was only partially overcome by agonist binding. The intertwined interactions described are likely to contribute to both the effects and side effects of Dox.
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http://dx.doi.org/10.1038/s41598-022-11994-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9110345PMC
May 2022

Endoplasmic reticulum stress in liver diseases.

Hepatology 2022 May 6. Epub 2022 May 6.

Shanghai Institute of Cardiovascular Diseases, Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China.

The endoplasmic reticulum (ER) is an intracellular organelle that fosters the correct folding of linear polypeptides and proteins, a process tightly governed by the ER-resident enzymes and chaperones. Failure to shape the proper 3-dimensional architecture of proteins culminates in the accumulation of misfolded or unfolded proteins within the ER, disturbs ER homeostasis, and leads to canonically defined ER stress. Recent studies have elucidated that cellular perturbations, such as lipotoxicity, can also lead to ER stress. In response to ER stress, the unfolded protein response (UPR) is activated to reestablish ER homeostasis ("adaptive UPR"), or, conversely, to provoke cell death when ER stress is overwhelmed and sustained ("maladaptive UPR"). It is well documented that ER stress contributes to the onset and progression of multiple hepatic pathologies including NAFLD, alcohol-associated liver disease, viral hepatitis, liver ischemia, drug toxicity, and liver cancers. Here, we review key studies dealing with the emerging role of ER stress and the UPR in the pathophysiology of liver diseases from cellular, murine, and human models. Specifically, we will summarize current available knowledge on pharmacological and non-pharmacological interventions that may be used to target maladaptive UPR for the treatment of nonmalignant liver diseases.
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http://dx.doi.org/10.1002/hep.32562DOI Listing
May 2022

BCG therapy downregulates HLA-I on malignant cells to subvert antitumor immune responses in bladder cancer.

J Clin Invest 2022 06;132(12)

INSERM U1015, Gustave Roussy, Université Paris-Saclay, Villejuif, France.

Patients with high-risk, nonmuscle-invasive bladder cancer (NMIBC) frequently relapse after standard intravesical bacillus Calmette-Guérin (BCG) therapy and may have a dismal outcome. The mechanisms of resistance to such immunotherapy remain poorly understood. Here, using cancer cell lines, freshly resected human bladder tumors, and samples from cohorts of patients with bladder cancer before and after BCG therapy, we demonstrate 2 distinct patterns of immune subversion upon BCG relapse. In the first pattern, intracellular BCG infection of cancer cells induced a posttranscriptional downregulation of HLA-I membrane expression via inhibition of autophagy flux. Patients with HLA-I-deficient cancer cells following BCG therapy had a myeloid immunosuppressive tumor microenvironment (TME) with epithelial-mesenchymal transition (EMT) characteristics and dismal outcomes. Conversely, patients with HLA-I-proficient cancer cells after BCG therapy presented with CD8+ T cell tumor infiltrates, upregulation of inflammatory cytokines, and immune checkpoint-inhibitory molecules. The latter patients had a very favorable outcome. We surmise that HLA-I expression in bladder cancers at relapse following BCG does not result from immunoediting but rather from an immune subversion process directly induced by BCG on cancer cells, which predicts a dismal prognosis. HLA-I scoring of cancer cells by IHC staining can be easily implemented by pathologists in routine practice to stratify future treatment strategies for patients with urothelial cancer.
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http://dx.doi.org/10.1172/JCI145666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9197524PMC
June 2022

Targeting HSP90 sensitizes pancreas carcinoma to PD-1 blockade.

Oncoimmunology 2022 25;11(1):2068488. Epub 2022 Apr 25.

Department of Surgery, UT Southwestern Medical Center, Dallas, Texas USA.

Interferon gamma (IFNG/IFNγ)-induced adaptive immune resistance remains a challenge for tumor therapy. We observed that the chaperone heat shock protein 90 (HSP90) stabilizes the transcription factor signal transducer and activator of transcription 1 (STAT1), resulting in IFNγ-induced expression of immunosuppressive indoleamine 2,3-dioxygenase 1 (IDO1) and programmed death-ligand 1 (PD-L1/CD274). Pharmacological inhibition of HSP90 enhances the efficacy of programmed cell death 1 (PDCD1/PD-1) targeting immunotherapy in suitable mouse models without any toxicity.
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http://dx.doi.org/10.1080/2162402X.2022.2068488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9045827PMC
May 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

A loss-of-function polymorphism in compromises therapeutic outcome in head and neck carcinoma patients.

Oncoimmunology 2022 17;11(1):2059878. Epub 2022 Apr 17.

Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, INSERM U1138, Centre de Recherche des Cordeliers, Institut Universitaire de France, Paris, France.

The anticancer immune response is shaped by immunogenic cell stress and death pathways. Thus, cancer cells can release danger-associated molecular patterns that act on pattern recognition receptors expressed by dendritic cells and their precursors to elicit an antitumor immune response. Here, we investigated the impact of single nucleotide polymorphisms (SNPs) in genes affecting this cancer-immunity dialogue in the context of head and neck squamous cell carcinoma (HNSCC). We observed that homozygosity for a loss-of-function SNP (rs2241880, leading to the substitution of a threonine residue in position 300 by an alanine) affecting autophagy related 16 like 1 is coupled to poor progression-free survival in platinum-treated HNSCC patients. This result was obtained on a cohort of patients enrolled at the Gustave Roussy Cancer Campus and was validated on an independent cohort of The Cancer Genome Atlas (TCGA). Homozygosity in rs2241880 is well known to predispose to Crohn's disease, and epidemiological associations between Crohn's disease and HNSCC have been reported at the levels of cancer incidence and prognosis. We speculate that rs2241880 might be partially responsible for this association.
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http://dx.doi.org/10.1080/2162402X.2022.2059878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9037530PMC
April 2022

Pro-ferroptotic fatty acid metabolism renders cancer cells immunogenic.

Trends Cancer 2022 Apr 22. Epub 2022 Apr 22.

Equipe labellisée par la Ligue contre le cancer, Université de Paris Cité, Sorbonne Université, INSERM UMR1138, Centre de Recherche des Cordeliers, Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy, Villejuif, France; Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, AP-HP, Paris, France; Institut Universitaire de France, 75005 Paris, France. Electronic address:

Tumor cell-intrinsic metabolic features can affect the cancer-immunity dialogue. In a recent paper published in Cancer Cell, Liao et al. demonstrate that IFNγ produced by T cells, together with arachidonic acid, can induce acyl-CoA synthetase long-chain family member 4 (ACSL4)-mediated ferroptosis, correlating with increased immunosurveillance and response to checkpoint blockade.
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http://dx.doi.org/10.1016/j.trecan.2022.04.002DOI Listing
April 2022

Targeting the gut and tumor microbiota in cancer.

Nat Med 2022 04 19;28(4):690-703. Epub 2022 Apr 19.

Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Microorganisms within the gut and other niches may contribute to carcinogenesis, as well as shaping cancer immunosurveillance and response to immunotherapy. Our understanding of the complex relationship between different host-intrinsic microorganisms, as well as the multifaceted mechanisms by which they influence health and disease, has grown tremendously-hastening development of novel therapeutic strategies that target the microbiota to improve treatment outcomes in cancer. Accordingly, the evaluation of a patient's microbial composition and function and its subsequent targeted modulation represent key elements of future multidisciplinary and precision-medicine approaches. In this Review, we outline the current state of research toward harnessing the microbiome to better prevent and treat cancer.
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http://dx.doi.org/10.1038/s41591-022-01779-2DOI Listing
April 2022

An obesogenic feedforward loop involving PPARγ, acyl-CoA binding protein and GABA receptor.

Cell Death Dis 2022 Apr 18;13(4):356. Epub 2022 Apr 18.

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.

Acyl-coenzyme-A-binding protein (ACBP), also known as a diazepam-binding inhibitor (DBI), is a potent stimulator of appetite and lipogenesis. Bioinformatic analyses combined with systematic screens revealed that peroxisome proliferator-activated receptor gamma (PPARγ) is the transcription factor that best explains the ACBP/DBI upregulation in metabolically active organs including the liver and adipose tissue. The PPARγ agonist rosiglitazone-induced ACBP/DBI upregulation, as well as weight gain, that could be prevented by knockout of Acbp/Dbi in mice. Moreover, liver-specific knockdown of Pparg prevented the high-fat diet (HFD)-induced upregulation of circulating ACBP/DBI levels and reduced body weight gain. Conversely, knockout of Acbp/Dbi prevented the HFD-induced upregulation of PPARγ. Notably, a single amino acid substitution (F77I) in the γ2 subunit of gamma-aminobutyric acid A receptor (GABAR), which abolishes ACBP/DBI binding to this receptor, prevented the HFD-induced weight gain, as well as the HFD-induced upregulation of ACBP/DBI, GABAR γ2, and PPARγ. Based on these results, we postulate the existence of an obesogenic feedforward loop relying on ACBP/DBI, GABAR, and PPARγ. Interruption of this vicious cycle, at any level, indistinguishably mitigates HFD-induced weight gain, hepatosteatosis, and hyperglycemia.
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http://dx.doi.org/10.1038/s41419-022-04834-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9016078PMC
April 2022

A hundred spotlights on microbiology: how microorganisms shape our lives.

Microb Cell 2022 Apr 4;9(4):72-79. Epub 2022 Apr 4.

Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria.

Viral, bacterial, fungal and protozoal biology is of cardinal importance for the evolutionary history of life, ecology, biotechnology and infectious diseases. Various microbiological model systems have fundamentally contributed to the understanding of molecular and cellular processes, including the cell cycle, cell death, mitochondrial biogenesis, vesicular fusion and autophagy, among many others. Microbial interactions within the environment have profound effects on many fields of biology, from ecological diversity to the highly complex and multifaceted impact of the microbiome on human health. Also, biotechnological innovation and corresponding industrial operations strongly depend on microbial engineering. With this wide range of impact in mind, the peer-reviewed and open access journal was founded in 2014 and celebrates its 100 issue this month. Here, we briefly summarize how the vast diversity of microbiological subjects influences our personal and societal lives and shortly review the milestones achieved by during the last years.
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http://dx.doi.org/10.15698/mic2022.04.773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8977871PMC
April 2022

Autophagy Alteration in ApoA-I Related Systemic Amyloidosis.

Int J Mol Sci 2022 Mar 23;23(7). Epub 2022 Mar 23.

Department of Chemical Sciences, University of Napoli Federico II, Complesso Universitario Monte Sant'Angelo, 80126 Napoli, Italy.

Amyloidoses are characterized by the accumulation and aggregation of misfolded proteins into fibrils in different organs, leading to cell death and consequent organ dysfunction. The specific substitution of Leu 75 for Pro in Apolipoprotein A-I protein sequence (ApoA-I; L75P-ApoA-I) results in late onset amyloidosis, where deposition of extracellular protein aggregates damages the normal functions of the liver. In this work, we describe that the autophagic process is inhibited in the presence of the L75P-ApoA-I amyloidogenic variant in stably transfected human hepatocyte carcinoma cells. The L75P-ApoA-I amyloidogenic variant alters the redox status of the cells, resulting into excessive mitochondrial stress and consequent cell death. Moreover, L75P-ApoA-I induces an impairment of the autophagic flux. Pharmacological induction of autophagy or transfection-enforced overexpression of the pro-autophagic transcription factor EB (TFEB) restores proficient proteostasis and reduces oxidative stress in these experimental settings, suggesting that pharmacological stimulation of autophagy could be a promising target to alleviate ApoA-I amyloidosis.
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http://dx.doi.org/10.3390/ijms23073498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8998969PMC
March 2022

Identification of HPCAL1 as a specific autophagy receptor involved in ferroptosis.

Autophagy 2022 Apr 10:1-21. Epub 2022 Apr 10.

Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA.

Selective macroautophagy/autophagy maintains cellular homeostasis through the lysosomal degradation of specific cellular proteins or organelles. The pro-survival effect of selective autophagy has been well-characterized, but the mechanism by which it drives cell death is still poorly understood. Here, we use a quantitative proteomic approach to identify HPCAL1 (hippocalcin like 1) as a novel autophagy receptor for the selective degradation of CDH2 (cadherin 2) during ferroptosis. HPCAL1-dependent CDH2 depletion increases susceptibility to ferroptotic death by reducing membrane tension and favoring lipid peroxidation. Site-directed mutagenesis aided by bioinformatic analyses revealed that the autophagic degradation of CDH2 requires PRKCQ (protein kinase C theta)-mediated HPCAL1 phosphorylation on Thr149, as well as a non-classical LC3-interacting region motif located between amino acids 46-51. An unbiased drug screening campaign involving 4208 small molecule compounds led to the identification of a ferroptosis inhibitor that suppressed HPCAL1 expression. The genetic or pharmacological inhibition of HPCAL1 prevented ferroptosis-induced tumor suppression and pancreatitis in suitable mouse models. These findings provide a framework for understanding how selective autophagy promotes ferroptotic cell death.: ANXA7: annexin A7; ARNTL: aryl hydrocarbon receptor nuclear translocator like; CCK8: cell counting kit-8; CDH2: cadherin 2; CETSAs: cellular thermal shift assays; CPT2: carnitine palmitoyltransferase 2; DAMP, danger/damage-associated molecular pattern; DPPH: 2,2-diphenyl-1-picrylhydrazyl; DFO: deferoxamine; EBNA1BP2: EBNA1 binding protein 2; EIF4G1: eukaryotic translation initiation factor 4 gamma 1; FBL: fibrillarin; FKBP1A: FKBP prolyl isomerase 1A; FTH1: ferritin heavy chain 1; GPX4: glutathione peroxidase 4; GSDMs: gasdermins; HBSS: Hanks' buffered salt solution; HMGB1: high mobility group box 1; HNRNPUL1: heterogeneous nuclear ribonucleoprotein U like 1; HPCAL1: hippocalcin like 1; H1-3/HIST1H1D: H1.3 linker histone, cluster member; IKE: imidazole ketone erastin; KD: knockdown; LDH: lactate dehydrogenase; LIR: LC3-interacting region; MAGOH: mago homolog, exon junction complex subunit; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; MDA: malondialdehyde; MLKL: mixed lineage kinase domain like pseudokinase; MPO: myeloperoxidase; MTOR: mechanistic target of rapamycin kinase; OE: overexpressing; OSTM1: osteoclastogenesis associated transmembrane protein 1; PRKC/PKC: protein kinase C; PRKAR1A: protein kinase cAMP-dependent type I regulatory subunit alpha; PRDX3: peroxiredoxin 3; PTGS2: prostaglandin-endoperoxide synthase 2; ROS: reactive oxygen species; SLC7A11: solute carrier family 7 member 11; SLC40A1: solute carrier family 40 member 1; SPTAN1: spectrin alpha, non-erythrocytic 1; STS: staurosporine; UBE2M: ubiquitin conjugating enzyme E2 M; ZYX: zyxin.
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http://dx.doi.org/10.1080/15548627.2022.2059170DOI Listing
April 2022
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