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1.
Nat Commun ; 13(1): 269, 2022 01 12.
Article in English | MEDLINE | ID: covidwho-1621240

ABSTRACT

A complete diagnostic autopsy is the gold-standard to gain insight into Coronavirus disease 2019 (COVID-19) pathogenesis. To delineate the in situ immune responses to SARS-CoV-2 viral infection, here we perform comprehensive high-dimensional transcriptional and spatial immune profiling in 22 COVID-19 decedents from Wuhan, China. We find TIM-3-mediated and PD-1-mediated immunosuppression as a hallmark of severe COVID-19, particularly in men, with PD-1+ cells being proximal rather than distal to TIM-3+ cells. Concurrently, lymphocytes are distal, while activated myeloid cells are proximal, to SARS-CoV-2 viral antigens, consistent with prevalent SARS-CoV-2 infection of myeloid cells in multiple organs. Finally, viral load positively correlates with specific immunosuppression and dendritic cell markers. In summary, our data show that SARS-CoV-2 viral infection induces lymphocyte suppression yet myeloid activation in severe COVID-19, so these two cell types likely have distinct functions in severe COVID-19 disease progression, and should be targeted differently for therapy.


Subject(s)
COVID-19/immunology , SARS-CoV-2/physiology , Aged , Autopsy , COVID-19/diagnosis , COVID-19/genetics , COVID-19/virology , China , Diagnosis , Female , Hepatitis A Virus Cellular Receptor 2/genetics , Hepatitis A Virus Cellular Receptor 2/immunology , Humans , Lymphocyte Activation , Lymphocytes/immunology , Male , Middle Aged , Myeloid Cells/immunology , Programmed Cell Death 1 Receptor/genetics , Programmed Cell Death 1 Receptor/immunology , SARS-CoV-2/immunology , Viral Load
2.
ESMO Open ; 7(1): 100359, 2022 02.
Article in English | MEDLINE | ID: covidwho-1560850

ABSTRACT

BACKGROUND: The durability of immunogenicity of SARS-CoV-2 vaccination in cancer patients remains to be elucidated. We prospectively evaluated the immunogenicity of the vaccine in triggering both the humoral and the cell-mediated immune response in cancer patients treated with anti-programmed cell death protein 1/programmed death-ligand 1 with or without chemotherapy 6 months after BNT162b2 vaccine. PATIENTS AND METHODS: In the previous study, 88 patients were enrolled, whereas the analyses below refer to the 60 patients still on immunotherapy at the time of the follow-up. According to previous SARS-CoV-2 exposure, patients were classified as SARS-CoV-2-naive (without previous SARS-CoV-2 exposure) and SARS-CoV-2-experienced (with previous SARS-CoV-2 infection). Neutralizing antibody (NT Ab) titer against the B.1.1 strain and total anti-spike immunoglobulin G concentration were quantified in serum samples. The enzyme-linked immunosorbent spot assay was used for quantification of anti-spike interferon-γ (IFN-γ)-producing cells/106 peripheral blood mononuclear cells. Fifty patients (83.0%) were on immunotherapy alone, whereas 10 patients (7%) were on chemo-immunotherapy. We analyzed separately patients on immunotherapy and patients on chemo-immunotherapy. RESULTS: The median T-cell response at 6 months was significantly lower than that measured at 3 weeks after vaccination [50 interquartile range (IQR) 20-118.8 versus 175 IQR 67.5-371.3 IFN-γ-producing cells/106 peripheral blood mononuclear cells; P < 0.0001]. The median reduction of immunoglobulin G concentration was 88% in SARS-CoV-2-naive subjects and 2.1% in SARS-CoV-2-experienced subjects. SARS-CoV-2 NT Ab titer was maintained in SARS-CoV-2-experienced subjects, whereas a significant decrease was observed in SARS-CoV-2-naive subjects (from median 1 : 160, IQR 1 : 40-1 : 640 to median 1 : 20, IQR 1 : 10-1 : 40; P < 0.0001). A weak correlation was observed between SARS-CoV-2 NT Ab titer and spike-specific IFN-γ-producing cells at both 6 months and 3 weeks after vaccination (r = 0.467; P = 0.0002 and r = 0.428; P = 0.0006, respectively). CONCLUSIONS: Our work highlights a reduction in the immune response in cancer patients, particularly in SARS-CoV-2-naive subjects. Our data support administering a third dose of COVID-19 vaccine to cancer patients treated with programmed cell death protein 1/programmed death-ligand 1 inhibitors.


Subject(s)
B7-H1 Antigen , COVID-19 , Immune Checkpoint Inhibitors , Neoplasms , Programmed Cell Death 1 Receptor , B7-H1 Antigen/antagonists & inhibitors , B7-H1 Antigen/immunology , /immunology , COVID-19/immunology , COVID-19/prevention & control , Follow-Up Studies , Humans , Immune Checkpoint Inhibitors/administration & dosage , Immune Checkpoint Inhibitors/immunology , Immunity, Cellular/drug effects , Immunity, Humoral/drug effects , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/immunology , Neoplasms/drug therapy , Neoplasms/immunology , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/immunology , SARS-CoV-2/immunology
3.
JCI Insight ; 6(24)2021 12 22.
Article in English | MEDLINE | ID: covidwho-1518198

ABSTRACT

A substantial proportion of patients who have recovered from coronavirus disease-2019 (COVID-19) experience COVID-19-related symptoms even months after hospital discharge. We extensively immunologically characterized patients who recovered from COVID-19. In these patients, T cells were exhausted, with increased PD-1+ T cells, as compared with healthy controls. Plasma levels of IL-1ß, IL-1RA, and IL-8, among others, were also increased in patients who recovered from COVID-19. This altered immunophenotype was mirrored by a reduced ex vivo T cell response to both nonspecific and specific stimulation, revealing a dysfunctional status of T cells, including a poor response to SARS-CoV-2 antigens. Altered levels of plasma soluble PD-L1, as well as of PD1 promoter methylation and PD1-targeting miR-15-5p, in CD8+ T cells were also observed, suggesting abnormal function of the PD-1/PD-L1 immune checkpoint axis. Notably, ex vivo blockade of PD-1 nearly normalized the aforementioned immunophenotype and restored T cell function, reverting the observed post-COVID-19 immune abnormalities; indeed, we also noted an increased T cell-mediated response to SARS-CoV-2 peptides. Finally, in a neutralization assay, PD-1 blockade did not alter the ability of T cells to neutralize SARS-CoV-2 spike pseudotyped lentivirus infection. Immune checkpoint blockade ameliorates post-COVID-19 immune abnormalities and stimulates an anti-SARS-CoV-2 immune response.


Subject(s)
COVID-19/complications , Cytokines/immunology , Immune Checkpoint Inhibitors/pharmacology , Programmed Cell Death 1 Receptor/immunology , SARS-CoV-2/immunology , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , B7-H1 Antigen/immunology , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Case-Control Studies , Cytokines/drug effects , DNA Methylation , Female , Humans , Immunophenotyping , In Vitro Techniques , Interleukin 1 Receptor Antagonist Protein/drug effects , Interleukin 1 Receptor Antagonist Protein/immunology , Interleukin-1beta/drug effects , Interleukin-1beta/immunology , Interleukin-8/drug effects , Interleukin-8/immunology , Male , MicroRNAs/metabolism , Middle Aged , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Promoter Regions, Genetic
4.
PLoS Pathog ; 17(10): e1009742, 2021 10.
Article in English | MEDLINE | ID: covidwho-1456098

ABSTRACT

Disease manifestations in COVID-19 range from mild to severe illness associated with a dysregulated innate immune response. Alterations in function and regeneration of dendritic cells (DCs) and monocytes may contribute to immunopathology and influence adaptive immune responses in COVID-19 patients. We analyzed circulating DC and monocyte subsets in 65 hospitalized COVID-19 patients with mild/moderate or severe disease from acute illness to recovery and in healthy controls. Persisting reduction of all DC subpopulations was accompanied by an expansion of proliferating Lineage-HLADR+ cells lacking DC markers. Increased frequency of CD163+ CD14+ cells within the recently discovered DC3 subpopulation in patients with more severe disease was associated with systemic inflammation, activated T follicular helper cells, and antibody-secreting cells. Persistent downregulation of CD86 and upregulation of programmed death-ligand 1 (PD-L1) in conventional DCs (cDC2 and DC3) and classical monocytes associated with a reduced capacity to stimulate naïve CD4+ T cells correlated with disease severity. Long-lasting depletion and functional impairment of DCs and monocytes may have consequences for susceptibility to secondary infections and therapy of COVID-19 patients.


Subject(s)
COVID-19/immunology , Dendritic Cells/immunology , Regeneration/immunology , SARS-CoV-2/immunology , Adult , Antigens, CD/immunology , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/pathology , COVID-19/pathology , Dendritic Cells/pathology , Female , Humans , Male , Middle Aged , Monocytes/immunology , Monocytes/pathology , Programmed Cell Death 1 Receptor/immunology
5.
J Immunol Methods ; 496: 113099, 2021 09.
Article in English | MEDLINE | ID: covidwho-1292808

ABSTRACT

Bispecific antibodies (BsAbs) are engineered to simultaneously bind two different antigens, and offer promising clinical outcomes for various diseases. The dual binding properties of BsAbs may enable superior efficacies and/or potencies compared to standard monoclonal antibodies (mAbs) or combination mAb therapies. Characterizing BsAb binding properties is critical during biotherapeutic development, where data is leveraged to predict efficacy and potency, assess critical quality attributes and improve antibody design. Traditional single-target, single-readout approaches (e.g., ELISA) have limited usefulness for interpreting complex bispecific binding, and double the benchwork. To address these deficiencies, we developed and implemented a new dual-target/readout binding assay that accurately dissects the affinities of both BsAb binding domains directly and simultaneously. This new assay uses AlphaPlex® technology, which eliminates traditional ELISA wash steps and can be miniaturized for automated workflows. The optimized BsAb AlphaPlex assay demonstrates 99-107% accuracy within a 50-150% linear range, and detected >50% binding degradation from photo- and thermal stress conditions. To the best of our knowledge, this is the first instance of a dual-target/readout BsAb AlphaPlex assay with GMP-suitable linear range, accuracy, specificity, and stability-indicating properties. As a highly customizable and efficient assay, BsAb AlphaPlex may be applicable to numerous bispecific formats and/or co-formulations against a variety of antigens beyond the clinical therapeutic space.


Subject(s)
Antibodies, Bispecific/immunology , Antibody Specificity , Antigens/immunology , CTLA-4 Antigen/immunology , Immunoassay , Programmed Cell Death 1 Receptor/immunology , Antibodies, Bispecific/metabolism , Antigen-Antibody Complex , Antigens/metabolism , Binding Sites, Antibody , Buffers , CTLA-4 Antigen/metabolism , Enzyme-Linked Immunosorbent Assay , Epitopes , Humans , Hydrogen-Ion Concentration , Kinetics , Predictive Value of Tests , Programmed Cell Death 1 Receptor/metabolism , Protein Binding , Reproducibility of Results
6.
PLoS One ; 16(6): e0251731, 2021.
Article in English | MEDLINE | ID: covidwho-1285198

ABSTRACT

Immunotherapy using checkpoint blockade (ICB) with antibodies such as anti-PD-1 has revolutionised the treatment of many cancers. Despite its use to treat COVID-19 patients and autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis, the effect of hydroxychloroquine (HCQ) on cancer immunotherapy has not been examined. In this study, remarkably, we find that HCQ alone, or in combination with azithromycin (AZ), at doses used to treat patients, decreased the therapeutic benefit of anti-PD-1 in cancer immunotherapy. No deleterious effect was seen on untreated tumors. Mechanistically, HCQ and HCQ/AZ inhibited PD-L1 expression on tumor cells, while specifically targeting the anti-PD-1 induced increase in progenitor CD8+CD44+PD-1+TCF1+ tumor infiltrating T cells (TILs) and the generation of CD8+CD44+PD-1+ effectors. Surprisingly, it also impaired the appearance of a subset of terminally exhausted CD8+ TILs. No effect was seen on the presence of CD4+ T cells, FoxP3+ regulatory T cells (Tregs), thymic subsets, B cells, antibody production, myeloid cells, or the vasculature of mice. This study indicates for the first time that HCQ and HCQ/AZ negatively impact the ability of anti-PD-1 checkpoint blockade to promote tumor rejection.


Subject(s)
Hydroxychloroquine/pharmacology , Immune Checkpoint Inhibitors/pharmacology , Immunotherapy , Programmed Cell Death 1 Receptor/immunology , Animals , Azithromycin/pharmacology , Cell Line, Tumor , Drug Antagonism , Immune Checkpoint Inhibitors/immunology , Melanoma/pathology , Mice , T-Lymphocytes/drug effects , T-Lymphocytes/immunology
7.
J Intern Med ; 290(3): 677-692, 2021 09.
Article in English | MEDLINE | ID: covidwho-1255442

ABSTRACT

BACKGROUND: Prognostic markers for disease severity and identification of therapeutic targets in COVID-19 are urgently needed. We have studied innate and adaptive immunity on protein and transcriptomic level in COVID-19 patients with different disease severity at admission and longitudinally during hospitalization. METHODS: Peripheral blood mononuclear cells (PBMCs) were collected at three time points from 31 patients included in the Norwegian SARS-CoV-2 cohort study and analysed by flow cytometry and RNA sequencing. Patients were grouped as either mild/moderate (n = 14), severe (n = 11) or critical (n = 6) disease in accordance with WHO guidelines and compared with patients with SARS-CoV-2-negative bacterial sepsis (n = 5) and healthy controls (n = 10). RESULTS: COVID-19 severity was characterized by decreased interleukin 7 receptor alpha chain (CD127) expression in naïve CD4 and CD8 T cells. Activation (CD25 and HLA-DR) and exhaustion (PD-1) markers on T cells were increased compared with controls, but comparable between COVID-19 severity groups. Non-classical monocytes and monocytic HLA-DR expression decreased whereas monocytic PD-L1 and CD142 expression increased with COVID-19 severity. RNA sequencing exhibited increased plasma B-cell activity in critical COVID-19 and yet predominantly reduced transcripts related to immune response pathways compared with milder disease. CONCLUSION: Critical COVID-19 seems to be characterized by an immune profile of activated and exhausted T cells and monocytes. This immune phenotype may influence the capacity to mount an efficient T-cell immune response. Plasma B-cell activity and calprotectin were higher in critical COVID-19 while most transcripts related to immune functions were reduced, in particular affecting B cells. The potential of these cells as therapeutic targets in COVID-19 should be further explored.


Subject(s)
COVID-19/genetics , COVID-19/immunology , Leukocytes, Mononuclear/immunology , Transcriptome , Adaptive Immunity , Adult , B-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Female , HLA-DR Antigens/immunology , Humans , Immunity, Innate , Interleukin-2 Receptor alpha Subunit/immunology , Interleukin-7/immunology , Leukocyte L1 Antigen Complex/blood , Male , Middle Aged , Monocytes/immunology , Phenotype , Programmed Cell Death 1 Receptor/immunology , SARS-CoV-2 , Severity of Illness Index , T-Lymphocytes, Regulatory/immunology , Thromboplastin/immunology , Thromboplastin/metabolism
8.
Cell Immunol ; 364: 104347, 2021 06.
Article in English | MEDLINE | ID: covidwho-1157177

ABSTRACT

Myeloid-derived suppressor cells (MDSC) are important immune-regulatory cells but their identification remains difficult. Here, we provide a critical view on selected surface markers, transcriptional and translational pathways commonly used to identify MDSC by specific, their developmental origin and new possibilities by transcriptional or proteomic profiling. Discrimination of MDSC from their non-suppressive counterparts is a prerequisite for the development of successful therapies. Understanding the switch mechanisms that direct granulocytic and monocytic development into a pro-inflammatory or anti-inflammatory direction will be crucial for therapeutic strategies. Manipulation of these myeloid checkpoints are exploited by tumors and pathogens, such as M. tuberculosis (Mtb), HIV or SARS-CoV-2, that induce MDSC for immune evasion. Thus, specific markers for MDSC identification may reveal also novel molecular candidates for therapeutic intervention at the level of MDSC.


Subject(s)
Biomarkers/metabolism , Gene Expression Profiling/methods , Myeloid-Derived Suppressor Cells/immunology , Proteomics/methods , Signal Transduction/immunology , Animals , B7-H1 Antigen/genetics , B7-H1 Antigen/immunology , B7-H1 Antigen/metabolism , COVID-19/immunology , COVID-19/prevention & control , COVID-19/virology , Cells, Cultured , Humans , Mice , Myeloid-Derived Suppressor Cells/metabolism , Neoplasms/genetics , Neoplasms/immunology , Neoplasms/metabolism , Programmed Cell Death 1 Receptor/genetics , Programmed Cell Death 1 Receptor/immunology , Programmed Cell Death 1 Receptor/metabolism , SARS-CoV-2/immunology , SARS-CoV-2/isolation & purification , SARS-CoV-2/physiology , Signal Transduction/genetics , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism
9.
J Immunother Cancer ; 9(3)2021 03.
Article in English | MEDLINE | ID: covidwho-1133309

ABSTRACT

While vaccines directed against the SARS-CoV-2 spike protein will have varying degrees of effectiveness in preventing SARS-CoV-2 infections, the severity of infection will be determined by multiple host factors including the ability of immune cells to lyse virus-infected cells. This review will discuss the complexity of both adaptive and innate immunomes and how a flow-based assay can detect up to 158 distinct cell subsets in the periphery. This assay has been employed to show the effect of age on differences in specific immune cell subsets, and the differences in the immunome between healthy donors and age-matched cancer patients. Also reviewed are the numerous soluble factors, in addition to cytokines, that may vary in the pathogenesis of SARS-CoV-2 infections and may also be employed to help define the effectiveness of a given vaccine or other antiviral agents. Various steroids have been employed in the management of autoimmune adverse events in cancer patients receiving immunotherapeutics and may be employed in the management of SARS-CoV-2 infections. The influence of steroids on multiple immune cells subsets will also be discussed.


Subject(s)
Adaptive Immunity/immunology , B-Lymphocytes/immunology , COVID-19/immunology , Dendritic Cells/immunology , Immunity, Innate/immunology , Killer Cells, Natural/immunology , Neoplasms/immunology , T-Lymphocytes/immunology , Age Factors , B7-H1 Antigen/immunology , CD40 Ligand/immunology , COVID-19/prevention & control , COVID-19 Vaccines/therapeutic use , Cytokines/immunology , Disease Susceptibility , Glucocorticoids/therapeutic use , Granzymes/immunology , Humans , Immune Checkpoint Inhibitors/therapeutic use , Immunosenescence/immunology , Myeloid-Derived Suppressor Cells/immunology , Neoplasms/drug therapy , Programmed Cell Death 1 Receptor/immunology , Proteome , SARS-CoV-2 , Severity of Illness Index , T-Lymphocyte Subsets/immunology , Tumor Necrosis Factor Receptor Superfamily, Member 7/immunology
10.
Oncoimmunology ; 9(1): 1789284, 2020 07 08.
Article in English | MEDLINE | ID: covidwho-1066080

ABSTRACT

Amid controversial reports that COVID-19 can be treated with a combination of the antimalarial drug hydroxychloroquine (HCQ) and the antibiotic azithromycin (AZI), a clinical trial (ONCOCOVID, NCT04341207) was launched at Gustave Roussy Cancer Campus to investigate the utility of this combination therapy in cancer patients. In this preclinical study, we investigated whether the combination of HCQ+AZI would be compatible with the therapeutic induction of anticancer immune responses. For this, we used doses of HCQ and AZI that affect whole-body physiology (as indicated by a partial blockade in cardiac and hepatic autophagic flux for HCQ and a reduction in body weight for AZI), showing that their combined administration did not interfere with tumor growth control induced by the immunogenic cell death inducer oxaliplatin. Moreover, the HCQ+AZI combination did not affect the capacity of a curative regimen (cisplatin + crizotinib + PD-1 blockade) to eradicate established orthotopic lung cancers in mice. In conclusion, it appears that HCQ+AZI does not interfere with the therapeutic induction of therapeutic anticancer immune responses.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Azithromycin/administration & dosage , COVID-19/drug therapy , Hydroxychloroquine/administration & dosage , Neoplasms/drug therapy , Animals , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Azithromycin/pharmacokinetics , COVID-19/immunology , COVID-19/virology , Cell Line, Tumor , Cisplatin/administration & dosage , Cisplatin/pharmacokinetics , Clinical Trials, Phase II as Topic , Crizotinib/administration & dosage , Crizotinib/pharmacokinetics , Disease Models, Animal , Drug Evaluation, Preclinical , Drug Interactions , Drug Therapy, Combination/methods , Female , France , Humans , Hydroxychloroquine/pharmacokinetics , Mice , Neoplasms/immunology , Oxaliplatin/administration & dosage , Oxaliplatin/pharmacokinetics , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/immunology , SARS-CoV-2/immunology , SARS-CoV-2/isolation & purification
11.
Sci Rep ; 11(1): 1864, 2021 01 21.
Article in English | MEDLINE | ID: covidwho-1042540

ABSTRACT

The ferret is a key animal model for investigating the pathogenicity and transmissibility of important human viruses, and for the pre-clinical assessment of vaccines. However, relatively little is known about the ferret immune system, due in part to a paucity of ferret-reactive reagents. In particular, T follicular helper (Tfh) cells are critical in the generation of effective humoral responses in humans, mice and other animal models but to date it has not been possible to identify Tfh in ferrets. Here, we describe the screening and development of ferret-reactive BCL6, CXCR5 and PD-1 monoclonal antibodies. We found two commercial anti-BCL6 antibodies (clone K112-91 and clone IG191E/A8) had cross-reactivity with lymph node cells from influenza-infected ferrets. We next developed two murine monoclonal antibodies against ferret CXCR5 (clone feX5-C05) and PD-1 (clone fePD-CL1) using a single B cell PCR-based method. We were able to clearly identify Tfh cells in lymph nodes from influenza infected ferrets using these antibodies. The development of ferret Tfh marker antibodies and the identification of ferret Tfh cells will assist the evaluation of vaccine-induced Tfh responses in the ferret model and the design of novel vaccines against the infection of influenza and other viruses, including SARS-CoV2.


Subject(s)
Antibodies, Monoclonal/immunology , Ferrets/immunology , High-Throughput Screening Assays/methods , T Follicular Helper Cells/immunology , Animals , Antibodies, Monoclonal/isolation & purification , COVID-19 Vaccines/immunology , Cross Reactions/immunology , Humans , Influenza Vaccines/immunology , Lymph Nodes/immunology , Mice , Programmed Cell Death 1 Receptor/immunology , Proto-Oncogene Proteins c-bcl-6/immunology , Receptors, CXCR5/immunology , Viral Vaccines/immunology
12.
J Clin Invest ; 130(12): 6477-6489, 2020 12 01.
Article in English | MEDLINE | ID: covidwho-1021209

ABSTRACT

Coronavirus disease 2019 (COVID-19) has emerged as a global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). So far, viral targets of cellular immunity and factors determining successful mounting of T cell responses are poorly defined. We therefore analyzed cellular responses to membrane, nucleocapsid, and spike proteins in individuals suffering from moderate or severe infection and in individuals who recovered from mild disease. We demonstrate that the CoV-2-specific CD4+ T helper cell response is directed against all 3 proteins with comparable magnitude, ex vivo proliferation, and portions of responding patients. However, individuals who died were more likely to have not mounted a cellular response to the proteins. Higher patient age and comorbidity index correlated with increased frequencies of CoV-2-specific CD4+ T cells, harboring higher portions of IL-2-secreting, but lower portions of IFN-γ-secreting, cells. Diminished frequencies of membrane protein-reactive IFN-γ+ T cells were particularly associated with higher acute physiology and chronic health evaluation II scores in patients admitted to intensive care. CoV-2-specific T cells exhibited elevated PD-1 expression in patients with active disease as compared with those individuals who recovered from previous mild disease. In summary, our data suggest a link between individual patient predisposition with respect to age and comorbidity and impairment of CoV-2-specific Th1-type cellular immunity, thereby supporting a concept of altered T cell function in at-risk patients.


Subject(s)
COVID-19/immunology , Interferon-gamma/immunology , Interleukin-2/immunology , Programmed Cell Death 1 Receptor/immunology , SARS-CoV-2/immunology , Th1 Cells/immunology , Adult , Age Factors , Aged , Aged, 80 and over , COVID-19/pathology , Disease Susceptibility , Female , Humans , Male , Middle Aged , Severity of Illness Index , Th1 Cells/pathology
13.
Eur J Immunol ; 50(12): 2013-2024, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-880266

ABSTRACT

The characterization of cell-mediated and humoral adaptive immune responses to SARS-CoV-2 is fundamental to understand COVID-19 progression and the development of immunological memory to the virus. In this study, we detected T-cells reactive to SARS-CoV-2 proteins M, S, and N, as well as serum virus-specific IgM, IgA, IgG, in nearly all SARS-CoV-2 infected individuals, but not in healthy donors. Virus-reactive T cells exhibited signs of in vivo activation, as suggested by the surface expression of immune-checkpoint molecules PD1 and TIGIT. Of note, we detected antigen-specific adaptive immune response both in asymptomatic and symptomatic SARS-CoV-2 infected subjects. More importantly, symptomatic patients displayed a significantly higher magnitude of both cell-mediated and humoral adaptive immune response to the virus, as compared to asymptomatic individuals. These findings suggest that an uncontrolled adaptive immune response contribute to the development of the life-threatening inflammatory phase of the disease. Finally, this study might open the way to develop effective vaccination strategies.


Subject(s)
Antibodies, Viral/immunology , COVID-19/immunology , Carrier State/immunology , Immunity, Humoral , SARS-CoV-2/immunology , T-Lymphocytes/immunology , Adult , Carrier State/virology , Female , Humans , Programmed Cell Death 1 Receptor/immunology , Receptors, Immunologic/immunology , Viral Proteins/immunology
14.
J Immunother Cancer ; 8(2)2020 10.
Article in English | MEDLINE | ID: covidwho-873575

ABSTRACT

Immune checkpoint inhibitors (ICI) block negative regulatory molecules, such as CTLA-4, PD-1 and PD-L1, in order to mount an antitumor response. T cells are important for antiviral defense, but it is not known whether patients with cancer treated with ICI are more or less vulnerable to viral infections such as COVID-19. Furthermore, immunosuppressive treatment of immune-related adverse events (irAE) may also impact infection risk. Rheumatic irAEs are often persistent, and can require long-term treatment with immunosuppressive agents. The aim of this study was to determine the incidence of COVID-19 infection and assess changes in ICI and immunosuppressive medication use among patients enrolled in a prospective rheumatic irAE registry during the height of the COVID-19 pandemic. On April 16 2020, following the 'surge' of COVID-19 infections in the New York Tri-State area, we sent a 23-question survey to 88 living patients enrolled in a single institutional registry of patients with rheumatic irAE. Questions addressed current cancer and rheumatic irAE status, ICI and immunosuppressant medication use, history of COVID-19 symptoms and/or diagnosed infection. A follow-up survey was sent out 6 weeks later. Sixty-five (74%) patients completed the survey. Mean age was 63 years, 59% were female, 70% had received anti-PD-(L)1 monotherapy and 80% had had an irAE affecting their joints. Six patients (10%) had definite or probable COVID-19, but all recovered uneventfully, including two still on ICI and on low-to-moderate dose prednisone. Of the 25 on ICI within the last 6 months, seven (28%) had their ICI held due to the pandemic. In patients on immunosuppression for irAE, none had changes made to those medications as a result of the pandemic. The incidence of COVID-19 was no higher in patients still on ICI. Ten percent of rheumatic irAE patients developed COVID-19 during the NY Tri-state 'surge' of March-April 2020. Oncologists held ICI in a quarter of the patients still on them, particularly women, those on anti-PD-(L)1 monotherapy, and those who had had a good cancer response. The incidence of COVID-19 was no higher on patients still on ICI. None of the patients on disease-modifying antirheumatic drugs or biological immunosuppressive medications developed COVID-19.


Subject(s)
Antineoplastic Agents, Immunological/adverse effects , Betacoronavirus/immunology , Coronavirus Infections/immunology , Immunosuppressive Agents/adverse effects , Neoplasms/drug therapy , Pneumonia, Viral/immunology , Rheumatic Diseases/drug therapy , Aged , B7-H1 Antigen/antagonists & inhibitors , B7-H1 Antigen/immunology , Betacoronavirus/pathogenicity , COVID-19 , COVID-19 Testing , CTLA-4 Antigen/antagonists & inhibitors , CTLA-4 Antigen/immunology , Clinical Decision-Making , Clinical Laboratory Techniques/statistics & numerical data , Coronavirus Infections/diagnosis , Coronavirus Infections/epidemiology , Coronavirus Infections/prevention & control , Female , Humans , Incidence , Male , Medical Oncology/standards , Medical Oncology/statistics & numerical data , Middle Aged , Neoplasms/immunology , New York City/epidemiology , Pandemics/prevention & control , Pneumonia, Viral/diagnosis , Pneumonia, Viral/epidemiology , Pneumonia, Viral/prevention & control , Practice Patterns, Physicians'/standards , Practice Patterns, Physicians'/statistics & numerical data , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/immunology , Prospective Studies , Registries/statistics & numerical data , Rheumatic Diseases/chemically induced , Rheumatic Diseases/epidemiology , Rheumatic Diseases/immunology , SARS-CoV-2 , Severity of Illness Index , Surveys and Questionnaires/statistics & numerical data
15.
J Immunother Cancer ; 8(2)2020 10.
Article in English | MEDLINE | ID: covidwho-873574

ABSTRACT

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has overwhelmed the health systems worldwide. Data regarding the impact of COVID-19 on cancer patients (CPs) undergoing or candidate for immune checkpoint inhibitors (ICIs) are lacking. We depicted the practice and adaptations in the management of patients with solid tumors eligible or receiving ICIs during the COVID-19 pandemic, with a special focus on Campania region. METHODS: This survey (25 questions), promoted by the young section of SCITO (Società Campana di ImmunoTerapia Oncologica) Group, was circulated among Italian young oncologists practicing in regions variously affected by the pandemic: high (group 1), medium (group 2) and low (group 3) prevalence of SARS-CoV-2-positive patients. For Campania region, the physician responders were split into those working in cancer centers (CC), university hospitals (UH) and general hospitals (GH). Percentages of agreement, among High (H) versus Medium (M) and versus Low (L) group for Italy and among CC, UH and GH for Campania region, were compared by using Fisher's exact tests for dichotomous answers and χ2 test for trends relative to the questions with 3 or more options. RESULTS: This is the first Italian study to investigate the COVID-19 impact on cancer immunotherapy, unique in its type and very clear in the results. The COVID-19 pandemic seemed not to affect the standard practice in the prescription and delivery of ICIs in Italy. Telemedicine was widely used. There was high consensus to interrupt immunotherapy in SARS-CoV-2-positive patients and to adopt ICIs with longer schedule interval. The majority of the responders tended not to delay the start of ICIs; there were no changes in supportive treatments, but some of the physicians opted for delaying surgeries (if part of patients' planned treatment approach). The results from responders in Campania did not differ significantly from the national ones. CONCLUSION: Our study highlights the efforts of Italian oncologists to maintain high standards of care for CPs treated with ICIs, regardless the regional prevalence of COVID-19, suggesting the adoption of similar solutions. Research on patients treated with ICIs and experiencing COVID-19 will clarify the safety profile to continue the treatments, thus informing on the most appropriate clinical conducts.


Subject(s)
Antineoplastic Agents, Immunological/administration & dosage , Betacoronavirus/immunology , Coronavirus Infections/epidemiology , Medical Oncology/statistics & numerical data , Neoplasms/drug therapy , Pneumonia, Viral/epidemiology , Adult , Antineoplastic Agents, Immunological/adverse effects , B7-H1 Antigen/antagonists & inhibitors , B7-H1 Antigen/immunology , Betacoronavirus/pathogenicity , COVID-19 , CTLA-4 Antigen/antagonists & inhibitors , CTLA-4 Antigen/immunology , Coronavirus Infections/immunology , Coronavirus Infections/prevention & control , Coronavirus Infections/transmission , Drug Prescriptions/statistics & numerical data , Female , Geography , Humans , Infection Control/standards , Italy/epidemiology , Male , Medical Oncology/standards , Neoplasms/immunology , Oncologists/statistics & numerical data , Pandemics/prevention & control , Pneumonia, Viral/immunology , Pneumonia, Viral/prevention & control , Pneumonia, Viral/transmission , Practice Patterns, Physicians'/standards , Practice Patterns, Physicians'/statistics & numerical data , Prevalence , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/immunology , SARS-CoV-2 , Surveys and Questionnaires/statistics & numerical data , Time-to-Treatment
16.
Cancer Treat Rev ; 90: 102109, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-842480

ABSTRACT

Treatment with immune-checkpoint inhibitors (ICIs) has shown efficacy against a variety of cancer types. The use of anti PD-1, anti PD-L1, and anti CTLA-4 antibodies is rapidly expanding. The side effects of ICIs are very different from conventional cytocidal anticancer and molecular target drugs, and may extend to the digestive organs, respiratory organs, thyroid gland, pituitary gland, skin, and others. Although the details of these adverse events are becoming increasingly apparent, much is unknown regarding the effects and adverse events related to infections. This review focuses specifically on the impact of ICIs on respiratory infections. The impact of ICIs on pathogens varies depending on the significance of the role of T-cell immunity in the immune response to the specific pathogen, as well as the different modes of infection (i.e., acute or chronic), although the impact of ICIs on the clinical outcome of infections in humans has not yet been well studied. Enhanced clearance of many pathogens has been shown because immune checkpoint inhibition activates T cells. In contrast, reactivation of tuberculosis associated with ICI use has been reported, and therefore caution is warranted. In COVID-19 pneumonia, ICI administration may lead to exacerbation; however, it is also possible that ICI may be used for the treatment of COVID-19. It has also been shown that ICI has potential in the treatment of intractable filamentous fungal infections. Therefore, expanded clinical applications are expected.


Subject(s)
Antineoplastic Agents, Immunological/adverse effects , Respiratory Tract Infections/chemically induced , Animals , Antineoplastic Agents, Immunological/administration & dosage , Antineoplastic Agents, Immunological/immunology , B7-H1 Antigen/antagonists & inhibitors , B7-H1 Antigen/immunology , CTLA-4 Antigen/antagonists & inhibitors , CTLA-4 Antigen/immunology , Humans , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/immunology , Randomized Controlled Trials as Topic , Respiratory Tract Infections/immunology
17.
Cancer Discov ; 10(10): 1432-1433, 2020 10.
Article in English | MEDLINE | ID: covidwho-723947
18.
Cell Mol Immunol ; 17(9): 995-997, 2020 09.
Article in English | MEDLINE | ID: covidwho-625131

Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/immunology , Molecular Targeted Therapy/methods , Pneumonia, Viral/immunology , Pneumonia/immunology , Severe Acute Respiratory Syndrome/immunology , Antiviral Agents/therapeutic use , Apyrase/antagonists & inhibitors , Apyrase/genetics , Apyrase/immunology , B-Lymphocytes/immunology , B-Lymphocytes/pathology , B7-H1 Antigen/antagonists & inhibitors , B7-H1 Antigen/genetics , B7-H1 Antigen/immunology , Betacoronavirus/immunology , COVID-19 , Case-Control Studies , Coronavirus Infections/drug therapy , Coronavirus Infections/genetics , Coronavirus Infections/virology , Gene Expression/drug effects , Humans , Immunologic Factors/therapeutic use , Killer Cells, Natural/drug effects , Killer Cells, Natural/immunology , Killer Cells, Natural/pathology , NK Cell Lectin-Like Receptor Subfamily C/antagonists & inhibitors , NK Cell Lectin-Like Receptor Subfamily C/genetics , NK Cell Lectin-Like Receptor Subfamily C/immunology , Pandemics , Pneumonia/drug therapy , Pneumonia/genetics , Pneumonia/virology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/genetics , Pneumonia, Viral/virology , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/genetics , Programmed Cell Death 1 Receptor/immunology , SARS-CoV-2 , Severe Acute Respiratory Syndrome/drug therapy , Severe Acute Respiratory Syndrome/genetics , Severe Acute Respiratory Syndrome/virology , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/pathology
19.
Eur J Cancer ; 135: 62-65, 2020 08.
Article in English | MEDLINE | ID: covidwho-605486

ABSTRACT

While confirmed cases of the deadly coronavirus disease 2019 (COVID-19) have exceeded 4.7 million globally, scientists are pushing forward with efforts to develop vaccines and treatments in an attempt to slow the pandemic and lessen the disease's damage. Although no proven effective therapies for treating patients with COVID-19 or for managing their complications currently exist, the rapidly expanding knowledge regarding severe acute respiratory syndrome coronavirus 2 and its interplay with hosts provides a significant number of potential drug targets and the potential to repurpose drugs already tested in other diseases. Herein, we report the biological rationale of immune-activating drugs and a brief summary of literature data on the potential therapeutic value of immune checkpoint inhibitors that have been recently tested beyond cancer treatment for their potential to restore cellular immunocompetence.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/drug therapy , Immunologic Factors/therapeutic use , Neoplasms/drug therapy , Pneumonia, Viral/drug therapy , Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Monoclonal, Humanized/therapeutic use , Apoptosis/drug effects , Apoptosis/immunology , B7-H1 Antigen/antagonists & inhibitors , B7-H1 Antigen/immunology , Betacoronavirus/immunology , COVID-19 , Coronavirus Infections/blood , Coronavirus Infections/immunology , Coronavirus Infections/virology , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/immunology , Humans , Immunologic Factors/pharmacology , Lymphopenia/blood , Lymphopenia/drug therapy , Lymphopenia/immunology , Lymphopenia/virology , Neoplasms/blood , Neoplasms/immunology , Pandemics , Pneumonia, Viral/blood , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/immunology , Randomized Controlled Trials as Topic , SARS-CoV-2 , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , Treatment Outcome
20.
Clin Cancer Res ; 26(16): 4201-4205, 2020 08 15.
Article in English | MEDLINE | ID: covidwho-599654

ABSTRACT

The potential immune intersection between COVID-19 disease and cancer therapy raises important practical clinical questions and highlights multiple scientific gaps to be filled. Among available therapeutic approaches to be considered, immune checkpoint inhibitors (ICI) seem to require major attention as they may act at the crossroads between cancer treatment and COVID-19 disease, due to their profound immunomodulatory activity. On the basis of available literature evidence, we suggest guidance to consider for treating physicians, and propose areas of clinical and preclinical investigation. Comprehensively, although with the necessary caution, ICI therapy seems to remain a suitable therapeutic option for patients with cancer during the COVID-19 pandemic.


Subject(s)
Antineoplastic Agents, Immunological/therapeutic use , Betacoronavirus/immunology , Coronavirus Infections/immunology , Neoplasms/drug therapy , Pneumonia, Viral/immunology , Antineoplastic Agents, Immunological/pharmacology , B7-H1 Antigen/antagonists & inhibitors , B7-H1 Antigen/immunology , COVID-19 , CTLA-4 Antigen/antagonists & inhibitors , CTLA-4 Antigen/immunology , Clinical Decision-Making , Clinical Trials as Topic , Coronavirus Infections/epidemiology , Coronavirus Infections/prevention & control , Coronavirus Infections/virology , Humans , Neoplasms/immunology , Pandemics/prevention & control , Pneumonia, Viral/epidemiology , Pneumonia, Viral/prevention & control , Pneumonia, Viral/virology , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/immunology , SARS-CoV-2 , Treatment Outcome
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