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1.
mBio ; 11(5)2020 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-32948688

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection induces a T cell response that most likely contributes to virus control in COVID-19 patients but may also induce immunopathology. Until now, the cytotoxic T cell response has not been very well characterized in COVID-19 patients. Here, we analyzed the differentiation and cytotoxic profile of T cells in 30 cases of mild COVID-19 during acute infection. SARS-CoV-2 infection induced a cytotoxic response of CD8+ T cells, but not CD4+ T cells, characterized by the simultaneous production of granzyme A and B as well as perforin within different effector CD8+ T cell subsets. PD-1-expressing CD8+ T cells also produced cytotoxic molecules during acute infection, indicating that they were not functionally exhausted. However, in COVID-19 patients over the age of 80 years, the cytotoxic T cell potential was diminished, especially in effector memory and terminally differentiated effector CD8+ cells, showing that elderly patients have impaired cellular immunity against SARS-CoV-2. Our data provide valuable information about T cell responses in COVID-19 patients that may also have important implications for vaccine development.IMPORTANCE Cytotoxic T cells are responsible for the elimination of infected cells and are key players in the control of viruses. CD8+ T cells with an effector phenotype express cytotoxic molecules and are able to perform target cell killing. COVID-19 patients with a mild disease course were analyzed for the differentiation status and cytotoxic profile of CD8+ T cells. SARS-CoV-2 infection induced a vigorous cytotoxic CD8+ T cell response. However, this cytotoxic profile of T cells was not detected in COVID-19 patients over the age of 80 years. Thus, the absence of a cytotoxic response in elderly patients might be a possible reason for the more frequent severity of COVID-19 in this age group than in younger patients.


Assuntos
Linfócitos T CD8-Positivos/patologia , Infecções por Coronavirus/imunologia , Pneumonia Viral/imunologia , Linfócitos T Citotóxicos/patologia , Idoso de 80 Anos ou mais , Antígenos CD/metabolismo , Betacoronavirus/patogenicidade , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/imunologia , Citotoxinas/metabolismo , Feminino , Humanos , Imunidade Celular , Masculino , Pessoa de Meia-Idade , Pandemias , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/patologia , Linfócitos T Citotóxicos/imunologia
2.
PLoS Pathog ; 16(9): e1008827, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32886721

RESUMO

Global burden of cervical cancer, the most common cause of mortality caused by human papillomavirus (HPV), is expected to increase during the next decade, mainly because current alternatives for HPV vaccination and cervical cancer screening programs are costly to be established in low-and-middle income countries. Recently, we described the development of the broadly protective, thermostable vaccine antigen Trx-8mer-OVX313 based on the insertion of eight different minor capsid protein L2 neutralization epitopes into a thioredoxin scaffold from the hyperthermophilic archaeon Pyrococcus furiosus and conversion of the resulting antigen into a nanoparticle format (median radius ~9 nm) upon fusion with the heptamerizing OVX313 module. Here we evaluated whether the engineered thioredoxin scaffold, in addition to humoral immune responses, can induce CD8+ T-cell responses upon incorporation of MHC-I-restricted epitopes. By systematically examining the contribution of individual antigen modules, we demonstrated that B-cell and T-cell epitopes can be combined into a single antigen construct without compromising either immunogenicity. While CD8+ T-cell epitopes had no influence on B-cell responses, the L2 polytope (8mer) and OVX313-mediated heptamerization of the final antigen significantly increased CD8+ T-cell responses. In a proof-of-concept experiment, we found that vaccinated mice remained tumor-free even after two consecutive tumor challenges, while unvaccinated mice developed tumors. A cost-effective, broadly protective vaccine with both prophylactic and therapeutic properties represents a promising option to overcome the challenges associated with prevention and treatment of HPV-caused diseases.


Assuntos
Antígenos de Neoplasias , Antígenos Virais , Proteínas Arqueais , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer , Imunidade Celular/efeitos dos fármacos , Nanopartículas , Papillomaviridae , Vacinas contra Papillomavirus , Pyrococcus furiosus/química , Tiorredoxinas , Neoplasias do Colo do Útero/imunologia , Animais , Antígenos de Neoplasias/química , Antígenos de Neoplasias/farmacologia , Antígenos Virais/química , Antígenos Virais/farmacologia , Proteínas Arqueais/química , Proteínas Arqueais/farmacologia , Linfócitos T CD8-Positivos/patologia , Vacinas Anticâncer/química , Vacinas Anticâncer/farmacologia , Epitopos de Linfócito B/química , Epitopos de Linfócito B/farmacologia , Epitopos de Linfócito T/química , Epitopos de Linfócito T/farmacologia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/química , Nanopartículas/uso terapêutico , Papillomaviridae/química , Papillomaviridae/imunologia , Vacinas contra Papillomavirus/química , Vacinas contra Papillomavirus/farmacologia , Tiorredoxinas/química , Tiorredoxinas/farmacologia , Neoplasias do Colo do Útero/virologia
3.
PLoS Pathog ; 16(9): e1008840, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32913355

RESUMO

P. vivax-infected Retics (iRetics) express human leukocyte antigen class I (HLA-I), are recognized by CD8+ T cells and killed by granulysin (GNLY) and granzymes. However, how Plasmodium infection induces MHC-I expression on Retics is unknown. In addition, whether GNLY helps control Plasmodium infection in vivo has not been studied. Here, we examine these questions using rodent infection with the P. yoelii 17XNL strain, which has tropism for Retics. Infection with P. yoelii caused extramedullary erythropoiesis, reticulocytosis and expansion of CD8+CD44+CD62L- IFN-γ-producing T cells that form immune synapses with iRetics. We now provide evidence that MHC-I expression by iRetic is dependent on IFN-γ-induced transcription of IRF-1, MHC-I and ß2-microglobulin (ß2-m) in erythroblasts. Consistently, CTLs from infected wild type (WT) mice formed immune synapses with iRetics in an IFN-γ- and MHC-I-dependent manner. When challenged with P. yoelii 17XNL, WT mice cleared parasitemia and survived, while IFN-γ KO mice remained parasitemic and all died. ß2-m KO mice that do not express MHC-I and have virtually no CD8+ T cells had prolonged parasitemia, and 80% survived. Because mice do not express GNLY, GNLY-transgenic mice can be used to assess the in vivo importance of GNLY. Parasite clearance was accelerated in GNLY-transgenic mice and depletion of CD8+ T cells ablated the GNLY-mediated resistance to P. yoelii. Altogether, our results indicate that in addition to previously described mechanisms, IFN-γ promotes host resistance to the Retic-tropic P. yoelii 17XNL strain by promoting MHC-I expression on iRetics that become targets for CD8+ cytotoxic T lymphocytes and GNLY.


Assuntos
Antígenos de Diferenciação de Linfócitos T/imunologia , Linfócitos T CD8-Positivos/imunologia , Interferon gama/imunologia , Malária/imunologia , Plasmodium yoelii/imunologia , Animais , Antígenos de Diferenciação de Linfócitos T/genética , Linfócitos T CD8-Positivos/patologia , Interferon gama/genética , Malária/genética , Malária/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout
4.
PLoS Pathog ; 16(9): e1008821, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32941545

RESUMO

MHC-I-restricted, virus-specific cytotoxic CD8+ T cells (CTLs) may control human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) replication via the recognition and killing of productively infected CD4+ T cells. Several studies in SIV-infected macaques suggest that CD8+ T cells may also decrease virus production by suppressing viral transcription. Here, we show that non-HIV-specific, TCR-activated non-cytolytic CD8+ T cells suppress HIV transcription via a virus- and MHC-independent immunoregulatory mechanism that modulates CD4+ T cell proliferation and activation. We also demonstrate that this CD8+ T cell-mediated effect promotes the survival of infected CD4+ T cells harboring integrated, inducible virus. Finally, we used RNA sequencing and secretome analyses to identify candidate cellular pathways that are involved in the virus-silencing mediated by these CD8+ T cells. This study characterizes a previously undescribed mechanism of immune-mediated HIV silencing that may be involved in the establishment and maintenance of the reservoir under antiretroviral therapy and therefore represent a major obstacle to HIV eradication.


Assuntos
Linfócitos T CD8-Positivos/imunologia , HIV-1/fisiologia , Antígenos de Histocompatibilidade Classe I/imunologia , Imunidade Inata , Transcrição Genética/imunologia , Replicação Viral/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Proliferação de Células , Humanos , Macaca
5.
Cancer Invest ; 38(7): 406-414, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32762373

RESUMO

BACKGROUND: Programmed death 1 (PD-1) and its ligand PD-L1 play a key dysfunction of T lymphocytes. The purpose of this study was to assess and compare the prognostic role of tumor- TILs and its relationship with PD-L1 expression in stage II and III colon cancer. METHODS: Immunohistochemisty was used to assess the densities of CD8+, CD4+, and FOXP3+ cells, and PD-L1 expression in intraepithelial tumor site from 58 stage II and III colon cancers. These were evaluated for association with histopathologic features and overall survival. RESULTS: PD-L1-positive tumors contained a higher number of CD8+ TILs with statistical significance (p = 0.001). CD4+ TILs showed positive correlation with PD-L1 expression (p = 0.034). There were no associations between PD-L1 expression and FOXP3+ TILs. Microsatellite instability (MSI)-high status (p = 0.001; Odd ration 18.0; 95% CI = 4.3-74.8) was the strongest prognostic factor along with mucinous/poor cell differentiation, CD8 and right tumor location was associated with PD-L1 expression (p = 0.024, 0.035 and 0.033, respectively). CONCLUSION: This study demonstrated that PD-L1 expression was associated with MSI-high, increased CD8+ TILs, mucinous and poor cell differentiation, and right-sided tumor location.


Assuntos
Antígeno B7-H1/metabolismo , Neoplasias do Colo/mortalidade , Neoplasias do Colo/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Feminino , Fatores de Transcrição Forkhead/metabolismo , Humanos , Imuno-Histoquímica , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Análise de Sobrevida
6.
PLoS One ; 15(8): e0236966, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32776968

RESUMO

Platelet-leukocyte aggregates (PLAs) are associated with increased thrombosis risk. The influence of PLA formation is especially important for cancer patients, since thrombosis accounts for approximately 10% of cancer-associated deaths. Our objective was to characterize and quantify PLAs in whole blood samples from lung cancer patients compared to healthy volunteers with the intent to analyze PLA formation in the context of lung cancer-associated thrombosis. Consenting lung cancer patients (57) and healthy volunteers (56) were enrolled at the Dana Cancer Center at the University of Toledo Health Science Campus. Peripheral blood samples were analyzed by flow cytometry. Patient medical history was reviewed through electronic medical records. Most importantly, we found lung cancer patients to have higher percentages of platelet-T cell aggregates (PTCAs) than healthy volunteers among both CD4+ T lymphocyte and CD8+ T lymphocyte populations. Our findings demonstrate that characterization of PTCAs may have clinical utility in differentiating lung cancer patients from healthy volunteers and stratifying lung cancer patients by history of thrombosis.


Assuntos
Plaquetas/patologia , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/complicações , Linfócitos T/patologia , Trombose/sangue , Trombose/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , Estudos de Casos e Controles , Agregação Celular , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Adulto Jovem
7.
Cancer Treat Rev ; 89: 102067, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32682248

RESUMO

BACKGROUND: Brain metastases are frequent complications in patients with non-small-cell lung cancer (NSCLC) associated with significant morbidity and poor prognosis. Our goal is to give a global overlook on clinical efficacy from immune checkpoint inhibitors in this setting and to review the role of biomarkers and molecular interactions in brain metastases from patients with NSCLC. METHODS: We reviewed clinical trials reporting clinical outcomes of patients with NSCLC with brain metastases as well as publications assessing the tumor microenvironment and the complex molecular interactions of tumor cells with immune and resident cells in brain metastases from NSCLC biopsies or preclinical models. RESULTS: Although limited data are available on immunotherapy in patients with brain metastases, immune checkpoint inhibitors alone or in combination with chemotherapy have shown promising intracranial efficacy and safety results. The underlying mechanism of action of immune checkpoint inhibitors in the brain niche and their influence on tumor microenvironment are still not known. Lower PD-L1 expression and less T CD8+ infiltration were found in brain metastases compared with matched NSCLC primary tumors, suggesting an immunosuppressive microenvironment in the brain. Reactive astrocytes and tumor associated macrophages are paramount in NSCLC brain metastases and play a role in promoting tumor progression and immune evasion. CONCLUSIONS: Discordances in the immune profile between primary tumours and brain metastases underscore differences in the tumour microenvironment and immune system interactions within the lung and brain niche. The characterization of immune phenotype of brain metastases and dissecting the interplay among immune cells and resident stromal cells along with cancer cells is crucial to unravel effective immunotherapeutic approaches in patients with NSCLC and brain metastases.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Animais , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Neoplasias Encefálicas/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Ativação Linfocitária , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Microambiente Tumoral/imunologia
8.
Nat Commun ; 11(1): 3434, 2020 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-32632085

RESUMO

The immune system of patients infected by SARS-CoV-2 is severely impaired. Detailed investigation of T cells and cytokine production in patients affected by COVID-19 pneumonia are urgently required. Here we show that, compared with healthy controls, COVID-19 patients' T cell compartment displays several alterations involving naïve, central memory, effector memory and terminally differentiated cells, as well as regulatory T cells and PD1+CD57+ exhausted T cells. Significant alterations exist also in several lineage-specifying transcription factors and chemokine receptors. Terminally differentiated T cells from patients proliferate less than those from healthy controls, whereas their mitochondria functionality is similar in CD4+ T cells from both groups. Patients display significant increases of proinflammatory or anti-inflammatory cytokines, including T helper type-1 and type-2 cytokines, chemokines and galectins; their lymphocytes produce more tumor necrosis factor (TNF), interferon-γ, interleukin (IL)-2 and IL-17, with the last observation implying that blocking IL-17 could provide a novel therapeutic strategy for COVID-19.


Assuntos
Betacoronavirus/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por Coronavirus/imunologia , Pneumonia Viral/imunologia , Subpopulações de Linfócitos T/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Senescência Celular , Infecções por Coronavirus/sangue , Infecções por Coronavirus/patologia , Síndrome da Liberação de Citocina , Citocinas/imunologia , Citocinas/metabolismo , Feminino , Humanos , Memória Imunológica , Itália/epidemiologia , Ativação Linfocitária , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/patologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/patologia , Células Th17/imunologia , Células Th17/metabolismo , Células Th17/patologia
9.
Nat Commun ; 11(1): 3410, 2020 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-32641700

RESUMO

COVID-19 is associated with 5.1% mortality. Although the virological, epidemiological, clinical, and management outcome features of COVID-19 patients have been defined rapidly, the inflammatory and immune profiles require definition as they influence pathogenesis and clinical expression of COVID-19. Here we show lymphopenia, selective loss of CD4+ T cells, CD8+ T cells and NK cells, excessive T-cell activation and high expression of T-cell inhibitory molecules are more prominent in severe cases than in those with mild disease. CD8+ T cells in patients with severe disease express high levels of cytotoxic molecules. Histochemical studies of lung tissue from one fatality show sub-anatomical distributions of SARS-CoV-2 RNA and massive infiltration of T cells and macrophages. Thus, aberrant activation and dysregulation of CD8+ T cells occur in patients with severe COVID-19 disease, an effect that might be for pathogenesis of SARS-CoV-2 infection and indicate that immune-based targets for therapeutic interventions constitute a promising treatment for severe COVID-19 patients.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus/imunologia , Biomarcadores/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Quimiotaxia de Leucócito , China/epidemiologia , Infecções por Coronavirus/sangue , Infecções por Coronavirus/virologia , Citocinas/sangue , Feminino , Humanos , Inflamação , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Contagem de Leucócitos , Pulmão/imunologia , Pulmão/virologia , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/virologia
10.
Front Immunol ; 11: 1638, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32695123

RESUMO

The SARS-CoV2 (COVID-19) pandemic and uncertainties in developing a vaccine have created an urgent need for new therapeutic approaches. A key question is whether it is possible to make rational predictions of new therapies based on the presently available scientific and medical information. In this regard, I have noticed an omission in the present analysis in the literature related to the exploitation of glycogen synthase kinase 3 (GSK-3) as a therapeutic approach. This is based on two key observations, that GSK-3 inhibitors can simultaneously block SARs viral replication, while boosting CD8+ adaptive T-cell and innate natural killer (NK) responses. Firstly, it is already clear that GSK-3 phosphorylation of SARs CoV1 N protein on key serine residues is needed for viral replication such that small molecule inhibitors (SMIs) of GSK-3 can inhibit viral replication. In comparing protein sequences, I show here that the key sites in the N protein of SARs CoV1 N for replication are conserved in SARs CoV2. This strongly suggests that GSK-3 SMIs will also inhibit SARs Cov2 replication. Secondly, we and others have previously documented that GSK-3 SMIs markedly enhance CD8+ cytolytic T-cell (CTL) and NK cell anti-viral effector functions leading to a reduction in both acute and chronic viral infections in mice. My hypothesis is that the repurposing of low-cost inhibitors of GSK-3 such as lithium will limit SARS-CoV2 infections by both reducing viral replication and potentiating the immune response against the virus. To date, there has been no mention of this dual connection between GSK-3 and SARs CoV2 in the literature. To my knowledge, no other drugs exist with the potential to simultaneously target both viral replication and immune response against SARs CoV2.


Assuntos
Betacoronavirus/fisiologia , Linfócitos T CD8-Positivos , Inibidores Enzimáticos/uso terapêutico , Quinase 3 da Glicogênio Sintase , Imunidade Celular/efeitos dos fármacos , Células Matadoras Naturais , Replicação Viral/efeitos dos fármacos , Linfócitos T CD8-Positivos/enzimologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/enzimologia , Infecções por Coronavirus/imunologia , Humanos , Células Matadoras Naturais/enzimologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/enzimologia , Pneumonia Viral/imunologia
11.
Cancer Immunol Immunother ; 69(10): 2157-2162, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32638080

RESUMO

Epidemiological evidence suggests that females have an advantage over males in cases of melanoma incidence, progression, and survival. However, the biological mechanisms underlying these sex differences remain unclear. With the knowledge that females generally have a more robust immune system than males, we investigated sex differences in melanoma progression in a B16-F10/BL6 syngeneic mouse model. We observed significantly less tumor volume and growth rate over 14 days in female mice compared to male mice. Furthermore, higher populations of CD4+ and CD8+ T cells, which indicate adaptive immune responses, were found in the circulating blood and tumors of females and corresponded with less tumor growth, and vice versa in males. Our results highlight a mouse model that represents melanoma progression in the human population and displays a higher immune response to melanoma in females compared to males. These findings suggest that the immune system may be one of the mechanisms responsible for sex differences in melanoma.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Modelos Animais de Doenças , Linfócitos do Interstício Tumoral/imunologia , Melanoma Experimental/imunologia , Neoplasias Cutâneas/imunologia , Linfócitos T Citotóxicos/imunologia , Animais , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , Feminino , Masculino , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Cutâneas/secundário , Linfócitos T Citotóxicos/patologia , Carga Tumoral , Células Tumorais Cultivadas
12.
Clin Immunol ; 217: 108486, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32479985

RESUMO

The lymphopenia exhibited in patients with COVID-19 has been associated with a worse prognosis in the development of the disease. To understand the factors associated with a worse evolution of COVID-19, we analyzed comorbidities, indicators of inflammation such as CRP and the ratio of neutrophils/lymphocytes, as well as the count of blood cells with T-lymphocyte subtypes in 172 hospitalized patients with COVID-19 pneumonia. Patients were grouped according to their needs for mechanical ventilation (ICU care) or not. Within the comorbidities studied, obesity was the only associated with greater severity and ICU admission. Both the percentage and the absolute number of neutrophils were higher in patients needing ICU care than non-ICU patients, whereas absolute lymphocyte count, and especially the percentage of lymphocytes, presented a deep decline in critical patients. There was no difference between the two groups of patients for CD4 T-lymphocytes, neither in percentage of lymphocyte nor in absolute number, however for CD8 T-cells the differences were significant for both parameters which were in decline in ICU patients. There was a firm correlation between the highest values of inflammation indicators with the decrease in percentage of CD8 T-lymphocytes. This effect was not seen with CD4 cells. Obesity together with lymphopenia, especially whether preferentially affects to CD8 T- lymphocytes, are factors that can predict a poor prognosis in patients with COVID-19.


Assuntos
Betacoronavirus/patogenicidade , Linfócitos T CD8-Positivos/patologia , Infecções por Coronavirus/imunologia , Linfopenia/imunologia , Neutrófilos/patologia , Obesidade/imunologia , Pneumonia Viral/imunologia , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus/imunologia , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD4-Positivos/virologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Estudos de Casos e Controles , Infecções por Coronavirus/complicações , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/terapia , Feminino , Humanos , Unidades de Terapia Intensiva , Contagem de Linfócitos , Linfopenia/complicações , Linfopenia/mortalidade , Linfopenia/terapia , Masculino , Pessoa de Meia-Idade , Neutrófilos/imunologia , Neutrófilos/virologia , Obesidade/complicações , Obesidade/mortalidade , Obesidade/terapia , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/mortalidade , Pneumonia Viral/terapia , Prognóstico , Respiração Artificial , Estudos Retrospectivos , Índice de Gravidade de Doença , Análise de Sobrevida
13.
Pediatr Infect Dis J ; 39(7): e100-e103, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32520888

RESUMO

BACKGROUND: To describe the characteristics of clinical manifestations of children with 2019 novel coronavirus (2019-nCoV) infection in Chongqing. METHODS: All 25 children with laboratory-confirmed 2019-nCoV infection by real-time reverse transcription-PCR (RNA-PCR) were admitted from the 4 designated treatment hospitals of 2019-nCoV in Chongqing from January 19 to March 12, 2020. Clinical data and epidemiologic history of these patients were retrospectively collected and analyzed. RESULTS: The diagnosis was confirmed through RNA-PCR testing. Among the 25 cases, 14 were males and 11 were females. The median age was 11.0 (6.3-14.5) years (range 0.6-17.0 years). All children were related to a family cluster outbreak, and 7 children (28%) with a travel or residence history in Hubei Province. These patients could be categorized into different clinical types, including 8 (32%) asymptomatic, 4 (16%) very mild cases and 13 (52%) common cases. No severe or critical cases were identified. The most common symptoms were cough (13 cases, 52%) and fever (6 cases, 24%). The duration time of clinical symptoms was 13.0 (8.0-25.0) days. In the 25 cases, on admission, 21 cases (84%) had normal white blood cell counts, while only 2 cases (8%) more than 10 × 10/L and 2 cases (8%) less than 4 × 10/L, respectively; 22 cases(88%) had normal CD4+ T lymphocyte counts, while in the remaining 3 cases(8%) this increased mildly; 23 cases had normal CD8+ T lymphocyte counts, while in the remaining 2 cases (8%) CD8+ T lymphocyte counts were mildly increased as well. All Lymphocyte counts were normal. There were no statistical differences of lab results between the groups of asymptomatic cases, mild cases and common cases. There were only 13 cases with abnormal CT imaging, most of which were located in the subpleural area of the bottom of the lung. All patients were treated with interferon, 6 cases combined with Ribavirin, and 12 cases combined with lopinavir or ritonavir. The days from onset to RNA turning negative was 15.20 ± 6.54 days. There was no significant difference of RNA turning negative between the groups of interferon, interferon plus ribavirin and interferon plus lopinavir or ritonavir treatment. All the cases recovered and were discharged from hospital. CONCLUSIONS: The morbidity of 2019-nCoV infection in children is lower than in adults and the clinical manifestations and inflammatory biomarkers in children are nonspecific and milder than that in adults. RNA-PCR test is still the most reliable diagnostic method, especially for asymptomatic patients.


Assuntos
Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/epidemiologia , Pneumonia Viral/diagnóstico , Pneumonia Viral/epidemiologia , Adolescente , Fatores Etários , Antivirais/uso terapêutico , Betacoronavirus/genética , Betacoronavirus/isolamento & purificação , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Criança , Pré-Escolar , China/epidemiologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/fisiopatologia , Tosse/virologia , Feminino , Febre/virologia , Humanos , Lactente , Lopinavir/uso terapêutico , Contagem de Linfócitos , Masculino , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/fisiopatologia , Prognóstico , Estudos Retrospectivos , Ribavirina/uso terapêutico , Ritonavir/uso terapêutico , Resultado do Tratamento
14.
PLoS Pathog ; 16(6): e1008555, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32579593

RESUMO

Exhaustion is a dysfunctional state of cytotoxic CD8+ T cells (CTL) observed in chronic infection and cancer. Current in vivo models of CTL exhaustion using chronic viral infections or cancer yield very few exhausted CTL, limiting the analysis that can be done on these cells. Establishing an in vitro system that rapidly induces CTL exhaustion would therefore greatly facilitate the study of this phenotype, identify the truly exhaustion-associated changes and allow the testing of novel approaches to reverse or prevent exhaustion. Here we show that repeat stimulation of purified TCR transgenic OT-I CTL with their specific peptide induces all the functional (reduced cytokine production and polyfunctionality, decreased in vivo expansion capacity) and phenotypic (increased inhibitory receptors expression and transcription factor changes) characteristics of exhaustion. Importantly, in vitro exhausted cells shared the transcriptomic characteristics of the gold standard of exhaustion, CTL from LCMV cl13 infections. Gene expression of both in vitro and in vivo exhausted CTL was distinct from T cell anergy. Using this system, we show that Tcf7 promoter DNA methylation contributes to TCF1 downregulation in exhausted CTL. Thus this novel in vitro system can be used to identify genes and signaling pathways involved in exhaustion and will facilitate the screening of reagents that prevent/reverse CTL exhaustion.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Metilação de DNA/imunologia , Fator 1-alfa Nuclear de Hepatócito/imunologia , Coriomeningite Linfocítica/imunologia , Vírus da Coriomeningite Linfocítica/imunologia , Regiões Promotoras Genéticas/imunologia , Animais , Linfócitos T CD8-Positivos/patologia , Fator 1-alfa Nuclear de Hepatócito/genética , Coriomeningite Linfocítica/genética , Coriomeningite Linfocítica/patologia , Vírus da Coriomeningite Linfocítica/genética , Camundongos , Camundongos Transgênicos , Transdução de Sinais/genética , Transdução de Sinais/imunologia
15.
J Cancer Res Clin Oncol ; 146(9): 2319-2327, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32592066

RESUMO

PURPOSE: Lymphocyte activation gene-3 (LAG3) is an immunosuppressive checkpoint molecule expressed on T cells. The frequency and distribution of LAG3 expression in oesophageal adenocarcinoma (EAC) is unknown. Aim of the study was the evaluation and distribution of LAG3 on tumour infiltrating lymphocytes (TILs) and correlation with clinico-pathological and molecular data. METHODS: We analysed tumor tissue samples using immunohistochemistry, multi-colour immunofluorescence and mRNA in-situ technology. The analyses were performed on a multi-spot tissue microarray (TMA) with 165 samples, followed by an evaluation on a single-spot TMA with 477 samples. These results were correlated with clinical and molecular tumour data. RESULTS: LAG3 expression on TILs was detectable in 10.5% on the multi-spot TMA and 11.4% on the single-spot TMA. There was a strong correlation between protein expression and mRNA expression (p < 0.001) in TILs. LAG 3 expression was correlated with CD4+ and CD8+ T-cells within the tumor (p < 0.001). LAG3 expression showed an improved overall survival (OS) compared to patients without LAG3 expression (median OS 70.2 vs. 26.9 months; p = 0.046). The effect was even clearer in the group of patients with tumour stages > pT2 (70.2 vs 25.0 months; p = 0.037). CONCLUSION: This is the first description of LAG3 expression on TILs in EAC, underscoring the importance of immunomodulation in EAC. Our data suggest an impact of LAG3 in a relevant subset of EAC. Therapeutic studies investigating the efficacy of LAG3 inhibition in EAC will also provide predictive evidence and relevance of the immunohistochemical determination of LAG3 expression.


Assuntos
Adenocarcinoma/metabolismo , Antígenos CD/metabolismo , Neoplasias Esofágicas/metabolismo , Linfócitos do Interstício Tumoral/metabolismo , RNA Mensageiro/metabolismo , Adenocarcinoma/patologia , Idoso , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Neoplasias Esofágicas/patologia , Feminino , Humanos , Ativação Linfocitária/fisiologia , Linfócitos do Interstício Tumoral/patologia , Masculino , Estadiamento de Neoplasias/métodos
16.
Oncology ; 98(10): 680-688, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32526753

RESUMO

BACKGROUND: In patients with colorectal cancer, the rate of recurrence increases as the histologic stage progresses. However, the prediction of recurrence in individual patients is difficult. Many studies have reported on the relation between outcomes and tissue-infiltrating lymphocytes (TILs). The aim of our study was to clarify the relation between TILs and oncologic outcomes in patients with colon cancer using propensity score matching analysis. METHODS: The study group comprised 513 patients with colon cancer who received curative resection. By using propensity score matching for sex, age, tumor location, T stage, N stage, histologic type, and adjuvant therapy as conventional prognostic factors, 61 patients with recurrence and 61 patients with no recurrence were selected. Hematoxylin-eosin staining and immunohistochemical staining using CD3, CD8, CD4, and FoxP3 were performed for lymphocytes in the primary tissue. The results were evaluated separately in the whole tumor, the central part, and the invasive margin. RESULTS: The median follow-up period was 53 months. Among the 513 patients, 70 had recurrence and 443 had no recurrence. In the comparison of outcomes between the 61 patients with recurrence and the 61 patients with no recurrence, univariate analysis showed that the disease-free survival rate was significantly higher among the patients with positive TILs in the whole tumor and in the invasive margin (p = 0.016 and p = 0.012, respectively) and with CD8+ cells in the central part (p = 0.039) than among those with negative results. A multivariate analysis showed that TILs in the invasive margin (hazard ratio 1.81; 95% confidence interval, 1.03-3.05; p = 0.037) and CD8+ cell density in the central part (hazard ratio 1.76; 95% confidence interval, 1.07-2.93; p = 0.023) were prognostic factors that were independent from conventional prognostic factors. CONCLUSIONS: In patients with curatively resected colon cancer, TILs in the invasive margin and CD8+ cell density in the central part may be prognostic factors suggesting host antitumor immune response.


Assuntos
Neoplasias do Colo/imunologia , Neoplasias do Colo/cirurgia , Linfócitos do Interstício Tumoral/imunologia , Recidiva Local de Neoplasia/imunologia , Idoso , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Neoplasias do Colo/patologia , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Linfócitos do Interstício Tumoral/patologia , Masculino , Análise Multivariada , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Pontuação de Propensão
17.
Pediatr Infect Dis J ; 39(7): e87-e90, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32379199

RESUMO

BACKGROUND: The outbreak of coronavirus disease 2019 (COVID-19) is becoming a global threat. However, our understanding of the clinical characteristics and treatment of critically ill pediatric patients and their ability of transmitting the coronavirus that causes COVID-19 still remains inadequate because only a handful pediatric cases of COVID-19 have been reported. METHODS: Epidemiology, clinical characteristics, treatment, laboratory data and follow-up information and the treatment of critically ill infant were recorded. RESULTS: The infant had life-threatening clinical features including high fever, septic shock, recurrent apnea, petechiae and acute kidney injury and persistent declined CD3+, CD4+ and CD8+ T cells. The duration of nasopharyngeal virus shedding lasted for 49 days even with the administration of lopinavir/ritonavir for 8 days. The CD3+, CD4+ and CD8+ T cells was partially recovered 68 days post onset of the disease. Accumulating of effector memory CD4+ T cells (CD4+TEM) was observed among T-cell compartment. The nucleic acid tests and serum antibody for the severe acute respiratory syndrome coronavirus 2 of the infant's mother who kept intimate contact with the infant were negative despite no strict personal protection. CONCLUSIONS: The persistent reduction of CD4+ and CD8+ T cells was the typical feature of critically ill infant with COVID-19. CD4+ and CD8+ T cells might play a key role in aggravating COVID-19 and predicts a more critical course in children. The prolonged nasopharyngeal virus shedding was related with the severity of respiratory injury. The transmission of SARS-CoV-2 from infant (even very critical cases) to adult might be unlikely.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por Coronavirus/imunologia , Pneumonia Viral/imunologia , Betacoronavirus/isolamento & purificação , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Estado Terminal , Humanos , Lactente , Lopinavir/uso terapêutico , Contagem de Linfócitos , Masculino , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Ritonavir/uso terapêutico , Eliminação de Partículas Virais/imunologia
18.
J Cancer Res Clin Oncol ; 146(8): 1979-1992, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32447483

RESUMO

PURPOSE: Esophageal cancer (EC) is one of the most lethal gastrointestinal malignancies. Immunotherapy is a promising treatment modality for this disease. However, broader implementation of EC immunotherapy has been discouraged because of insufficient understanding of tumor interactions with the immune system. As with other malignancies, the current research on EC focuses on deciphering the immune cell signatures within the tumor microenvironment. However, the disease-elicited immune cell profiles in the paratumoral compartments are largely unknown. METHODS: We examined the immune cell signatures in 62 tissue samples from 16 EC patients in different esophageal tissue compartments: tumor tissue, peritumoral tissue, healthy esophageal tissue, and adjacent lymph nodes. We analyzed the proportions and distribution patterns of NK cells and CD4+ and CD8+ T cells as well as their death receptor (FasR, FasR/DR3)-expressing subpopulations. The analyzed data were then compared and correlated with the patients' clinicopathological data. RESULTS: We found that the FasR+ NK cells, CD4+ and CD8+ T cells infiltrated lymph nodes at the lowest levels and that the FasR+DR3+ CD4+ T cells were enhanced in tumors. The comparisons with the clinicopathological data revealed a major impact of active smoking on the reduction in paratumoral NK cells and the upregulation of FasR in tumor-infiltrating NK and CD8+ T cells. The lymph node metastatic stage, tumor stage, and Mandard grade correlated with the compartmental proportions of the evaluated immune cells. CONCLUSION: The novel association of the disease state with tumoral and paratumoral immune cell signatures suggests new possibilities for personalized immunotherapy for EC patients.


Assuntos
Neoplasias Esofágicas/imunologia , Neoplasias Esofágicas/terapia , Linfócitos/imunologia , Adenocarcinoma/imunologia , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Idoso , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Estudos de Casos e Controles , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/imunologia , Carcinoma de Células Escamosas do Esôfago/patologia , Carcinoma de Células Escamosas do Esôfago/terapia , Feminino , Humanos , Imunoterapia/métodos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Linfonodos/imunologia , Linfonodos/patologia , Linfócitos/patologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Masculino , Pessoa de Meia-Idade , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/patologia , Receptor fas/imunologia
19.
PLoS One ; 15(5): e0233795, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32469992

RESUMO

Understanding the effects of obesity on the immune profile of renal cell carcinoma (RCC) patients is critical, given the rising use of immunotherapies to treat advanced disease and recent reports of differential cancer immunotherapy outcomes with obesity. Here, we evaluated multiple immune parameters at the genetic, soluble protein, and cellular levels in peripheral blood and renal tumors from treatment-naive clear cell RCC (ccRCC) subjects (n = 69), to better understand the effects of host obesity (Body Mass Index "BMI" ≥ 30 kg/m2) in the absence of immunotherapy. Tumor-free donors (n = 38) with or without obesity were used as controls. In our ccRCC cohort, increasing BMI was associated with decreased percentages of circulating activated PD-1+CD8+ T cells, CD14+CD16neg classical monocytes, and Foxp3+ regulatory T cells (Tregs). Only CD14+CD16neg classical monocytes and Tregs were reduced when obesity was examined as a categorical variable. Obesity did not alter the percentages of circulating IFNγ+ CD8 T cells or IFNγ+, IL-4+, or IL-17A+ CD4 T cells in ccRCC subjects. Of 38 plasma proteins analyzed, six (CCL3, IL-1ß, IL-1RA, IL-10, IL-17, and TNFα) were upregulated specifically in ccRCC subjects with obesity versus tumor-free controls with obesity. IGFBP-1 was uniquely decreased in ccRCC subjects with obesity versus non-obese ccRCC subjects. Immunogenetic profiling of ccRCC tumors revealed that 93% of examined genes were equivalently expressed and no changes in cell type scores were found in stage-matched tumors from obesity category II/III versus normal weight (BMI ≥ 35 kg/m2 versus 18.5-24.9 kg/m2, respectively) subjects. Intratumoral PLGF and VEGF-A proteins were elevated in ccRCC subjects with obesity. Thus, in ccRCC patients with localized disease, obesity is not associated with widespread detrimental alterations in systemic or intratumoral immune profiles. The effects of combined obesity and immunotherapy administration on immune parameters remains to be determined.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Carcinoma de Células Renais/imunologia , Neoplasias Renais/imunologia , Monócitos/imunologia , Obesidade/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD8-Positivos/patologia , Estudos de Coortes , Citocinas/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos/patologia , Linfócitos T Reguladores/patologia , Adulto Jovem
20.
Nat Med ; 26(6): 909-918, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32472114

RESUMO

PD-1 blockade has transformed the management of advanced clear cell renal cell carcinoma (ccRCC), but the drivers and resistors of the PD-1 response remain incompletely elucidated. Here, we analyzed 592 tumors from patients with advanced ccRCC enrolled in prospective clinical trials of treatment with PD-1 blockade by whole-exome and RNA sequencing, integrated with immunofluorescence analysis, to uncover the immunogenomic determinants of the therapeutic response. Although conventional genomic markers (such as tumor mutation burden and neoantigen load) and the degree of CD8+ T cell infiltration were not associated with clinical response, we discovered numerous chromosomal alterations associated with response or resistance to PD-1 blockade. These advanced ccRCC tumors were highly CD8+ T cell infiltrated, with only 27% having a non-infiltrated phenotype. Our analysis revealed that infiltrated tumors are depleted of favorable PBRM1 mutations and enriched for unfavorable chromosomal losses of 9p21.3, as compared with non-infiltrated tumors, demonstrating how the potential interplay of immunophenotypes with somatic alterations impacts therapeutic efficacy.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Nivolumabe/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Apresentação do Antígeno/genética , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/patologia , Deleção Cromossômica , Cromossomos Humanos Par 6 , Cromossomos Humanos Par 9/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Proteínas de Ligação a DNA/genética , Feminino , Imunofluorescência , Deleção de Genes , Genômica , Antígenos de Histocompatibilidade Classe II/genética , Histona Desmetilases/genética , Histona-Lisina N-Metiltransferase/genética , Humanos , Neoplasias Renais/genética , Neoplasias Renais/imunologia , Neoplasias Renais/patologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Masculino , Pessoa de Meia-Idade , Mutação , PTEN Fosfo-Hidrolase/genética , Prognóstico , Complexo de Endopeptidases do Proteassoma/genética , Análise de Sequência de RNA , Serina-Treonina Quinases TOR/genética , Fatores de Transcrição/genética , Proteína 1 do Complexo Esclerose Tuberosa/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Sequenciamento Completo do Exoma
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