Publications by authors named "Antoine Lafarge"

14 Publications

  • Page 1 of 1

Severe infections in recipients of cancer immunotherapy: what intensivists need to know.

Curr Opin Crit Care 2022 Aug 11. Epub 2022 Aug 11.

Medical Intensive Care Unit, Saint-Louis Teaching Hospital, Public Assistance Hospitals of Paris, Paris, France.

Purpose Of Review: Given the increased number of cancer patients admitted in the ICU and the growing importance of immunotherapy in their therapeutic arsenal, intensivists will be increasingly confronted to patients treated with immunotherapies who will present with complications, infectious and immunologic.

Recent Findings: Apart from their specific immunologic toxicities, cancer immunotherapy recipients also have specific immune dysfunction and face increased infectious risks that may lead to intensive care unit admission.

Summary: Chimeric antigen receptor T-cell therapy is associated with profound immunosuppression and the risks of bacterial, fungal and viral infections vary according to the time since infusion.Immune checkpoint blockers are associated with an overall favorable safety profile but associations of checkpoint blockers and corticosteroids and immunosuppressive drugs prescribed to treat immune-related adverse events are associated with increased risks of bacterial and fungal infections.The T-cell engaging bispecific therapy blinatumomab causes profound B-cell aplasia, hypogammaglobulinemia and neutropenia, but seems to be associated with fewer infectious adverse events compared with standard intensive chemotherapy.Lastly, intravesical administration of Bacillus Calmette-Guérin (BCG) can lead to disseminated BCGitis and severe sepsis requiring a specific antibiotherapy, often associated with corticosteroid treatment.
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http://dx.doi.org/10.1097/MCC.0000000000000978DOI Listing
August 2022

Characteristics and outcome of adults with severe autoimmune hemolytic anemia admitted to the intensive care unit: Results from a large French observational study.

Am J Hematol 2022 Jul 24. Epub 2022 Jul 24.

Department of Internal Medicine, National Reference Center for Adult' Immune Cytopenias, Henri Mondor University Hospital, Université Paris-Est Créteil, Assistance Publique Hôpitaux de Paris, Créteil, France.

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http://dx.doi.org/10.1002/ajh.26665DOI 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

Severe hemophagocytic lymphohistiocytosis in kidney transplant recipient: the etiology is on the tip of the tongue!

Intensive Care Med 2022 Jun 18. Epub 2022 Jun 18.

Medical Intensive Care Unit, Hôpital Saint-Louis, Assistance Publique Hôpitaux de Paris (APHP), Université de Paris, 1 avenue Claude Vellefaux, 75010, Paris, France.

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http://dx.doi.org/10.1007/s00134-022-06757-3DOI Listing
June 2022

Cancer Induces a Stress Ileopathy Depending on β-Adrenergic Receptors and Promoting Dysbiosis that Contributes to Carcinogenesis.

Cancer Discov 2022 04;12(4):1128-1151

Laboratoire de Pathologie Clinique et Expérimental, FHU OncoAge et Biobanque BB-0033-00025, CHU de Nice, Université Côte d'Azur, Nice, France.

Gut dysbiosis has been associated with intestinal and extraintestinal malignancies, but whether and how carcinogenesis drives compositional shifts of the microbiome to its own benefit remains an open conundrum. Here, we show that malignant processes can cause ileal mucosa atrophy, with villous microvascular constriction associated with dominance of sympathetic over cholinergic signaling. The rapid onset of tumorigenesis induced a burst of REG3γ release by ileal cells, and transient epithelial barrier permeability that culminated in overt and long-lasting dysbiosis dominated by Gram-positive Clostridium species. Pharmacologic blockade of β-adrenergic receptors or genetic deficiency in Adrb2 gene, vancomycin, or cohousing of tumor bearers with tumor-free littermates prevented cancer-induced ileopathy, eventually slowing tumor growth kinetics. Patients with cancer harbor distinct hallmarks of this stress ileopathy dominated by Clostridium species. Hence, stress ileopathy is a corollary disease of extraintestinal malignancies requiring specific therapies.

Significance: Whether gut dysbiosis promotes tumorigenesis and how it controls tumor progression remain open questions. We show that 50% of transplantable extraintestinal malignancies triggered a β-adrenergic receptor-dependent ileal mucosa atrophy, associated with increased gut permeability, sustained Clostridium spp.-related dysbiosis, and cancer growth. Vancomycin or propranolol prevented cancer-associated stress ileopathy. This article is highlighted in the In This Issue feature, p. 873.
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http://dx.doi.org/10.1158/2159-8290.CD-21-0999DOI Listing
April 2022

Coronavirus disease 2019 in immunocompromised patients: a comprehensive review of coronavirus disease 2019 in hematopoietic stem cell recipients.

Curr Opin Crit Care 2022 02;28(1):83-89

Medical Intensive Care Unit, Saint Louis Hospital, Assistance Publique Hôpitaux de Paris (APHP), University de Paris, Paris, France.

Purpose Of Review: Immunocompromised patients are notably vulnerable to severe coronavirus disease 2019. This review summarizes COVID-19 features and outcomes in autologous and allogeneic hematopoietic stem cell transplantation (HSCT) recipients.

Recent Findings: Recent findings suggest that HSCT recipients exhibit a high burden of comorbidities and COVID-19 clinical features almost similar to the general COVID population. Furthermore, HSCT recipients exhibit a protracted SARS-CoV-2 shedding, prolonging duration of symptoms and promoting the generation of highly mutated viruses. Last, most of studies report a higher COVID-19 mortality in HSCT recipients, mainly driven by age, comorbidities, time from transplantation, and immunosuppression because of both treatments and underlying hematological malignancy.

Summary: Further studies are warranted to determine the proper impact of HSCT-related immune disorders on COVID-19 outcomes, and to evaluate specific treatments and vaccination strategy in this high-risk population. Taken together, those findings emphasize the need for more rigorous surveillance and preemptive measures for all HSCT recipients.
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http://dx.doi.org/10.1097/MCC.0000000000000907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8711307PMC
February 2022

Metabolic features of cancer cells impact immunosurveillance.

J Immunother Cancer 2021 06;9(6)

Equipe 11 labellisée par la Ligue contre le Cancer, Université de Paris, Sorbonne Université, INSERM U1138, Centre de Recherche des Cordeliers, INSERM, Paris, France

Background: Tumors rewire their metabolism to achieve robust anabolism and resistance against therapeutic interventions like cisplatin treatment. For example, a prolonged exposure to cisplatin causes downregulation of pyridoxal kinase (PDXK), the enzyme that generates the active vitamin B6, and upregulation of poly ADP-ribose (PAR) polymerase-1 (PARP1) activity that requires a supply of nicotinamide (vitamin B3) adenine dinucleotide. We investigated the impact of the levels of PDXK and PAR on the local immunosurveillance (ie, density of the antigen presenting cells and adaptive immune response by CD8 T lymphocytes) in two different tumor types.

Methods: Tumors from patients with locally advanced cervical carcinoma (LACC) and non-small cell lung cancer (NSCLC) were stained for PAR, PDXK, dendritic cell lysosomal associated membrane glycoprotein (DC-LAMP) and CD8 T cell infiltration. Their correlations and prognostic impact were assessed. Cisplatin-resistant NSCLC cell clones isolated from Lewis-lung cancer (LLC) cells were evaluated for PAR levels by immunoblot. Parental (PAR) and cisplatin-resistant (PAR) clones were subcutaneously injected into the flank of C57BL/6 mice. Tumors were harvested to evaluate their immune infiltration by flow cytometry.

Results: The infiltration of tumors by CD8 T and DC-LAMP cells was associated with a favorable overall survival in patients with LACC (p=0.006 and p=0.008, respectively) and NSCLC (p<0.001 for both CD8 T and DC-LAMP cells). We observed a positive correlation between PDXK expression and the infiltration by DC-LAMP (R=0.44, p=0.02 in LACC, R=0.14, p=0.057 in NSCLC), and a negative correlation between PAR levels and CD8 T lymphocytes (R=-0.39, p=0.034 in LACC, R=-0.18, p=0.017 in NSCLC). PARP1 is constitutively hyperactivated in cisplatin-resistant LLC cells manifesting elevated intracellular levels of poly(ADP-ribosyl)ated proteins (PAR). Tumors formed by such cancer cells injected into immunocompetent mice were scarcely infiltrated by CD8 T (p=0.028) and antigen presenting cells (p=0.086).

Conclusions: Oncometabolic features can impact local immunosurveillance, providing new functional links between cisplatin resistance and therapeutic failure.
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http://dx.doi.org/10.1136/jitc-2021-002362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8231002PMC
June 2021

Effects of acyl-coenzyme A binding protein (ACBP)/diazepam-binding inhibitor (DBI) on body mass index.

Cell Death Dis 2021 06 9;12(6):599. Epub 2021 Jun 9.

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

In mice, the plasma concentrations of the appetite-stimulatory and autophagy-inhibitory factor acyl-coenzyme A binding protein (ACBP, also called diazepam-binding inhibitor, DBI) acutely increase in response to starvation, but also do so upon chronic overnutrition leading to obesity. Here, we show that knockout of Acbp/Dbi in adipose tissue is sufficient to prevent high-fat diet-induced weight gain in mice. We investigated ACBP/DBI plasma concentrations in several patient cohorts to discover a similar dual pattern of regulation. In relatively healthy subjects, ACBP/DBI concentrations independently correlated with body mass index (BMI) and age. The association between ACBP/DBI and BMI was lost in subjects that underwent major weight gain in the subsequent 3-9 years, as well as in advanced cancer patients. Voluntary fasting, undernutrition in the context of advanced cancer, as well as chemotherapy were associated with an increase in circulating ACBP/DBI levels. Altogether, these results support the conclusion that ACBP/DBI may play an important role in body mass homeostasis as well as in its failure.
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http://dx.doi.org/10.1038/s41419-021-03864-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190068PMC
June 2021

Two different patterns of lymphocyte alterations in critically ill COVID-19 patients.

Intern Emerg Med 2021 08 1;16(5):1411-1414. Epub 2021 Jan 1.

Medical Intensive Care Unit, Saint Louis Hospital, Assistance Publique Hôpitaux de Paris (APHP), University de Paris, 1 Avenue Claude Vellefaux, 75010, Paris, France.

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http://dx.doi.org/10.1007/s11739-020-02575-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775726PMC
August 2021

Metabolic and psychiatric effects of acyl coenzyme A binding protein (ACBP)/diazepam binding inhibitor (DBI).

Cell Death Dis 2020 07 6;11(7):502. Epub 2020 Jul 6.

Fondation FondaMental, Créteil, France.

Acyl coenzyme A binding protein (ACBP), also known as diazepam binding inhibitor (DBI) is a multifunctional protein with an intracellular action (as ACBP), as well as with an extracellular role (as DBI). The plasma levels of soluble ACBP/DBI are elevated in human obesity and reduced in anorexia nervosa. Accumulating evidence indicates that genetic or antibody-mediated neutralization of ACBP/DBI has anorexigenic effects, thus inhibiting food intake and inducing lipo-catabolic reactions in mice. A number of anorexiants have been withdrawn from clinical development because of their side effects including an increase in depression and suicide. For this reason, we investigated the psychiatric impact of ACBP/DBI in mouse models and patient cohorts. Intravenously (i.v.) injected ACBP/DBI protein conserved its orexigenic function when the protein was mutated to abolish acyl coenzyme A binding, but lost its appetite-stimulatory effect in mice bearing a mutation in the γ2 subunit of the γ-aminobutyric acid (GABA) A receptor (GABAR). ACBP/DBI neutralization by intraperitoneal (i.p.) injection of a specific mAb blunted excessive food intake in starved and leptin-deficient mice, but not in ghrelin-treated animals. Neither i.v. nor i.p. injected anti-ACBP/DBI antibody affected the behavior of mice in the dark-light box and open-field test. In contrast, ACBP/DBI increased immobility in the forced swim test, while anti-ACBP/DBI antibody counteracted this sign of depression. In patients diagnosed with therapy-resistant bipolar disorder or schizophrenia, ACBP/DBI similarly correlated with body mass index (BMI), not with the psychiatric diagnosis. Patients with high levels of ACBP/DBI were at risk of dyslipidemia and this effect was independent from BMI, as indicated by multivariate analysis. In summary, it appears that ACBP/DBI neutralization has no negative impact on mood and that human depression is not associated with alterations in ACBP/DBI concentrations.
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http://dx.doi.org/10.1038/s41419-020-2716-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338362PMC
July 2020

Predictive factors of severe infections in patients with systemic necrotizing vasculitides: data from 733 patients enrolled in five randomized controlled trials of the French Vasculitis Study Group.

Rheumatology (Oxford) 2020 09;59(9):2250-2257

Department of Internal Medicine.

Objectives: Infections remain a major cause of morbidity and mortality in systemic necrotizing vasculitides (SNV). We aimed to identify factors predicting severe infections (SI) in SNV.

Methods: Data from five randomized controlled trials (RCTs) enrolling 733 patients were pooled. The primary end point was the occurrence of SI, defined by the need of a hospitalization and/or intravenous anti-infectious treatment and/or leading to death.

Results: After a median follow-up of 5.2 (interquartile range 3-9.7) years, 148 (20.2%) patients experienced 189 SI, and 98 (66.2%) presented their first SI within the first 2 years. Median interval from inclusion to SI was 14.9 (4.3-51.7) months. Age ≥65 years (hazard ratio (HR) 1.49 [1.07-2.07]; P=0.019), pulmonary involvement (HR 1.82 [1.26-2.62]; P=0.001) and Five Factor Score ≥1 (HR 1.21 [1.03-1.43]; P=0.019) were independent predictive factors of SI. Regarding induction therapy, the occurrence of SI was associated with the combination of GCs and CYC (HR 1.51 [1.03-2.22]; P = 0.036), while patients receiving only GCs were less likely to present SI (HR 0.69 [0.44-1.07]; P = 0.096). Finally, occurrence of SI had a significant negative impact on survival (P<0.001).

Conclusion: SI in SNV are frequent and impact mortality. Age, pulmonary involvement and Five Factor Score are baseline independent predictors of SI. No therapeutic regimen was significantly associated with SI but patients receiving glucocorticoids and CYC as induction tended to have more SI.
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http://dx.doi.org/10.1093/rheumatology/kez575DOI Listing
September 2020

Prognosis of autoimmune hemolytic anemia in critically ill patients.

Ann Hematol 2019 Mar 10;98(3):589-594. Epub 2018 Dec 10.

Medical Intensive Care Unit, Saint-Louis Teaching Hospital, AP-HP, Paris, France.

Patients with autoimmune hemolytic anemia (AIHA) may require intensive care unit (ICU) admission. In order to describe the characteristics of AIHA patients in ICU and identify prognosis factors, clinical and biological data from 44 patients admitted in one ICU between 2002 and 2015 were retrospectively analyzed. The main reasons for ICU admission were profound anemia without any organ failure in 19 patients (either for safer transfusion or continuous monitoring only). Twenty-five (57%) patients had a past history of hemopathy. Twenty patients presented with a direct anti-globulin test (DAT) positive for immunoglobulin G (DAT-IgG) only (46%), 8 with a DAT positive for both IgG and complement (DAT-IgG+C) (36%), and 16 with a DAT positive for complement only (DAT-IgG+C) (18%). Corticosteroids and rituximab were administered to respectively 44 (100%) and 12 (25%) patients. Red blood cell transfusion was required in 28 (64%) patients. Ten (23%) patients received vasopressors. Renal replacement therapy was necessary in 14 (31.8%) patients. Thirteen (30%) patients died in the ICU. There was no difference between survivors and non-survivors regarding associated comorbidities like hemopathy (18/31 [58%] vs. 7/13 [54%], p = 0.80). In decedents, age was higher (72 years [57.8-76.3] vs. 50 years [34.3-64], p < 0.01) and organ dysfunctions were more severe at day 1 (SOFA 8 [7-11] vs. 5.5 [3-7], p < 0.01). Patients with a DAT-IgG displayed poorer outcome in comparison with patients with DAT-IgG+C/C (hospital mortality 69% vs. 36%, p = 0.04). Mortality rate of AIHA patients requiring ICU admission is consequential and appears to be impacted by age, organ failures, and DAT-IgG.
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http://dx.doi.org/10.1007/s00277-018-3553-9DOI Listing
March 2019
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