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1.
Nat Commun ; 11(1): 4227, 2020 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-32839441

RESUMO

In hematopoietic cell transplants, alloreactive T cells mediate the graft-versus-leukemia (GVL) effect. However, leukemia relapse accounts for nearly half of deaths. Understanding GVL failure requires a system in which GVL-inducing T cells can be tracked. We used such a model wherein GVL is exclusively mediated by T cells that recognize the minor histocompatibility antigen H60. Here we report that GVL fails due to insufficient H60 presentation and T cell exhaustion. Leukemia-derived H60 is inefficiently cross-presented whereas direct T cell recognition of leukemia cells intensifies exhaustion. The anti-H60 response is augmented by H60-vaccination, an agonist αCD40 antibody (FGK45), and leukemia apoptosis. T cell exhaustion is marked by inhibitory molecule upregulation and the development of TOX+ and CD39-TCF-1+ cells. PD-1 blockade diminishes exhaustion and improves GVL, while blockade of Tim-3, TIGIT or LAG3 is ineffective. Of all interventions, FGK45 administration at the time of transplant is the most effective at improving memory and naïve T cell anti-H60 responses and GVL. Our studies define important causes of GVL failure and suggest strategies to overcome them.


Assuntos
Apresentação do Antígeno/imunologia , Efeito Enxerto vs Leucemia/imunologia , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia/terapia , Linfócitos T/imunologia , Animais , Células Cultivadas , Humanos , Leucemia/imunologia , Leucemia/patologia , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Antígenos de Histocompatibilidade Menor/genética , Antígenos de Histocompatibilidade Menor/imunologia , Antígenos de Histocompatibilidade Menor/metabolismo , Recidiva , Transplante Homólogo
2.
Front Immunol ; 11: 1949, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32849654

RESUMO

After the 1918 flu pandemic, the world is again facing a similar situation. However, the advancement in medical science has made it possible to identify that the novel infectious agent is from the coronavirus family. Rapid genome sequencing by various groups helped in identifying the structure and function of the virus, its immunogenicity in diverse populations, and potential preventive measures. Coronavirus attacks the respiratory system, causing pneumonia and lymphopenia in infected individuals. Viral components like spike and nucleocapsid proteins trigger an immune response in the host to eliminate the virus. These viral antigens can be either recognized by the B cells or presented by MHC complexes to the T cells, resulting in antibody production, increased cytokine secretion, and cytolytic activity in the acute phase of infection. Genetic polymorphism in MHC enables it to present some of the T cell epitopes very well over the other MHC alleles. The association of MHC alleles and its downregulated expression has been correlated with disease severity against influenza and coronaviruses. Studies have reported that infected individuals can, after recovery, induce strong protective responses by generating a memory T-cell pool against SARS-CoV and MERS-CoV. These memory T cells were not persistent in the long term and, upon reactivation, caused local damage due to cross-reactivity. So far, the reports suggest that SARS-CoV-2, which is highly contagious, shows related symptoms in three different stages and develops an exhaustive T-cell pool at higher loads of viral infection. As there are no specific treatments available for this novel coronavirus, numerous small molecular drugs that are being used for the treatment of diseases like SARS, MERS, HIV, ebola, malaria, and tuberculosis are being given to COVID-19 patients, and clinical trials for many such drugs have already begun. A classical immunotherapy of convalescent plasma transfusion from recovered patients has also been initiated for the neutralization of viremia in terminally ill COVID-19 patients. Due to the limitations of plasma transfusion, researchers are now focusing on developing neutralizing antibodies against virus particles along with immuno-modulation of cytokines like IL-6, Type I interferons (IFNs), and TNF-α that could help in combating the infection. This review highlights the similarities of the coronaviruses that caused SARS and MERS to the novel SARS-CoV-2 in relation to their pathogenicity and immunogenicity and also focuses on various treatment strategies that could be employed for curing COVID-19.


Assuntos
Betacoronavirus/genética , Infecções por Coronavirus/imunologia , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Pneumonia Viral/imunologia , Vírus da SARS/genética , Síndrome Respiratória Aguda Grave/imunologia , Animais , Apresentação do Antígeno/imunologia , Antivirais/uso terapêutico , Betacoronavirus/química , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Citocinas/biossíntese , Genoma Viral , Humanos , Evasão da Resposta Imune , Imunização Passiva/métodos , Camundongos , Coronavírus da Síndrome Respiratória do Oriente Médio/química , Pandemias , Filogenia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Vírus da SARS/química , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Síndrome Respiratória Aguda Grave/virologia , Linfócitos T/imunologia , Replicação Viral
3.
PLoS Pathog ; 16(8): e1008685, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32745153

RESUMO

Smallpox and monkeypox pose severe threats to human health. Other orthopoxviruses are comparably virulent in their natural hosts, including ectromelia, the cause of mousepox. Disease severity is linked to an array of immunomodulatory proteins including the B22 family, which has homologs in all pathogenic orthopoxviruses but not attenuated vaccine strains. We demonstrate that the ectromelia B22 member, C15, is necessary and sufficient for selective inhibition of CD4+ but not CD8+ T cell activation by immunogenic peptide and superantigen. Inhibition is achieved not by down-regulation of surface MHC- II or co-stimulatory protein surface expression but rather by interference with antigen presentation. The appreciable outcome is interference with CD4+ T cell synapse formation as determined by imaging studies and lipid raft disruption. Consequently, CD4+ T cell activating stimulus shifts to uninfected antigen-presenting cells that have received antigen from infected cells. This work provides insight into the immunomodulatory strategies of orthopoxviruses by elucidating a mechanism for specific targeting of CD4+ T cell activation, reflecting the importance of this cell type in control of the virus.


Assuntos
Apresentação do Antígeno/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Vírus da Ectromelia/imunologia , Ectromelia Infecciosa/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Proteínas Virais/imunologia , Animais , Ectromelia Infecciosa/metabolismo , Ectromelia Infecciosa/virologia , Feminino , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Proteínas Virais/metabolismo , Virulência
4.
Nat Commun ; 11(1): 4035, 2020 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-32788578

RESUMO

Polyphosphates are linear polymers and ubiquitous metabolites. Bacterial polyphosphates are long chains of hundreds of phosphate units. Here, we report that mouse survival of peritoneal Escherichia coli sepsis is compromised by long-chain polyphosphates, and improves with bacterial polyphosphatekinase deficiency or neutralization using recombinant exopolyphosphatase. Polyphosphate activities are chain-length dependent, impair pathogen clearance, antagonize phagocyte recruitment, diminish phagocytosis and decrease production of iNOS and cytokines. Macrophages bind and internalize polyphosphates, in which their effects are independent of P2Y1 and RAGE receptors. The M1 polarization driven by E. coli derived LPS is misdirected by polyphosphates in favor of an M2 resembling phenotype. Long-chain polyphosphates modulate the expression of more than 1800 LPS/TLR4-regulated genes in macrophages. This interference includes suppression of hundreds of type I interferon-regulated genes due to lower interferon production and responsiveness, blunted STAT1 phosphorylation and reduced MHCII expression. In conclusion, prokaryotic polyphosphates disturb multiple macrophage functions for evading host immunity.


Assuntos
Infecções por Escherichia coli/imunologia , Infecções por Escherichia coli/microbiologia , Escherichia coli/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Imunidade Inata , Polifosfatos/metabolismo , Animais , Apresentação do Antígeno/imunologia , Polaridade Celular , Antígenos de Histocompatibilidade Classe II/metabolismo , Interferon Tipo I/metabolismo , Lipopolissacarídeos , Macrófagos/imunologia , Macrófagos/microbiologia , Camundongos Endogâmicos C57BL , Células Mieloides/imunologia , Fenótipo , Sepse/imunologia , Análise de Sobrevida , Transcriptoma/genética
5.
J Exp Med ; 217(12)2020 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-32820330

RESUMO

Type I interferons (IFN-I) are a major antiviral defense and are critical for the activation of the adaptive immune system. However, early viral clearance by IFN-I could limit antigen availability, which could in turn impinge upon the priming of the adaptive immune system. In this study, we hypothesized that transient IFN-I blockade could increase antigen presentation after acute viral infection. To test this hypothesis, we infected mice with viruses coadministered with a single dose of IFN-I receptor-blocking antibody to induce a short-term blockade of the IFN-I pathway. This resulted in a transient "spike" in antigen levels, followed by rapid antigen clearance. Interestingly, short-term IFN-I blockade after coronavirus, flavivirus, rhabdovirus, or arenavirus infection induced a long-lasting enhancement of immunological memory that conferred improved protection upon subsequent reinfections. Short-term IFN-I blockade also improved the efficacy of viral vaccines. These findings demonstrate a novel mechanism by which IFN-I regulate immunological memory and provide insights for rational vaccine design.


Assuntos
Imunogenicidade da Vacina/imunologia , Interferon Tipo I/antagonistas & inibidores , Interferon-alfa/imunologia , Receptor de Interferon alfa e beta/imunologia , Vacinas Virais/imunologia , Infecção por Zika virus/imunologia , Zika virus/imunologia , Animais , Anticorpos Bloqueadores/imunologia , Anticorpos Bloqueadores/farmacologia , Anticorpos Antivirais/imunologia , Apresentação do Antígeno/imunologia , Linfócitos T CD8-Positivos/metabolismo , Células Dendríticas/imunologia , Modelos Animais de Doenças , Expressão Gênica/imunologia , Células HEK293 , Humanos , Memória Imunológica , Interferon-alfa/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor de Interferon alfa e beta/genética , Transfecção , Infecção por Zika virus/virologia
6.
Proc Natl Acad Sci U S A ; 117(30): 17727-17736, 2020 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-32665441

RESUMO

Erythrocytes naturally capture certain bacterial pathogens in circulation, kill them through oxidative stress, and present them to the antigen-presenting cells (APCs) in the spleen. By leveraging this innate immune function of erythrocytes, we developed erythrocyte-driven immune targeting (EDIT), which presents nanoparticles from the surface of erythrocytes to the APCs in the spleen. Antigenic nanoparticles were adsorbed on the erythrocyte surface. By engineering the number density of adsorbed nanoparticles, (i.e., the number of nanoparticles loaded per erythrocyte), they were predominantly delivered to the spleen rather than lungs, which is conventionally the target of erythrocyte-mediated delivery systems. Presentation of erythrocyte-delivered nanoparticles to the spleen led to improved antibody response against the antigen, higher central memory T cell response, and lower regulatory T cell response, compared with controls. Enhanced immune response slowed down tumor progression in a prophylaxis model. These findings suggest that EDIT is an effective strategy to enhance systemic immunity.


Assuntos
Apresentação do Antígeno/imunologia , Antígenos/imunologia , Eritrócitos/imunologia , Imunização , Animais , Formação de Anticorpos/imunologia , Antígenos/química , Biomimética , Linhagem Celular Tumoral , Células Dendríticas/imunologia , Feminino , Humanos , Camundongos , Nanopartículas , Baço/imunologia , Vacinação , Vacinas , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Proc Natl Acad Sci U S A ; 117(25): 14342-14353, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32513716

RESUMO

Immature T cells undergo a process of positive selection in the thymus when their new T cell receptor (TCR) engages and signals in response to self-peptides. As the T cell matures, a slew of negative regulatory molecules, including the inhibitory surface glycoprotein CD5, are up-regulated in proportion to the strength of the self-peptide signal. Together these regulators dampen TCR-proximal signaling and help avoid any subsequent peripheral activation of T cells by self-peptides. Paradoxically, antigen-specific T cells initially expressing more CD5 (CD5hi) have been found to better persist as effector/memory cells after a peripheral challenge. The molecular mechanisms underlying such a duality in CD5 function is not clear. We found that CD5 alters the basal activity of the NF-κB signaling in resting peripheral T cells. When CD5 was conditionally ablated, T cells were unable to maintain higher expression of the cytoplasmic NF-κB inhibitor IκBα. Consistent with this, resting CD5hi T cells expressed more of the NF-κB p65 protein than CD5lo cells, without significant increases in transcript levels, in the absence of TCR signals. This posttranslationally stabilized cellular NF-κB depot potentially confers a survival advantage to CD5hi T cells over CD5lo ones. Taken together, these data suggest a two-step model whereby the strength of self-peptide-induced TCR signal lead to the up-regulation of CD5, which subsequently maintains a proportional reserve of NF-κB in peripheral T cells poised for responding to agonistic antigen-driven T cell activation.


Assuntos
Antígenos CD5/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/imunologia , Inibidor de NF-kappaB alfa/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , Linfócitos T/imunologia , Transferência Adotiva , Animais , Apresentação do Antígeno/imunologia , Antígenos CD5/genética , Linhagem Celular Tumoral , Separação Celular , Sobrevivência Celular/imunologia , Feminino , Citometria de Fluxo , Lipopolissacarídeos/imunologia , Ativação Linfocitária , Camundongos , Camundongos Knockout , Modelos Animais , Cultura Primária de Células , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Transdução de Sinais/imunologia , Linfócitos T/metabolismo , Linfócitos T/transplante , Timo/citologia , Timo/crescimento & desenvolvimento , Timo/imunologia , Fator de Transcrição RelA/metabolismo , Regulação para Cima
8.
Nature ; 581(7806): 100-105, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32376951

RESUMO

Immune evasion is a major obstacle for cancer treatment. Common mechanisms of evasion include impaired antigen presentation caused by mutations or loss of heterozygosity of the major histocompatibility complex class I (MHC-I), which has been implicated in resistance to immune checkpoint blockade (ICB) therapy1-3. However, in pancreatic ductal adenocarcinoma (PDAC), which is resistant to most therapies including ICB4, mutations that cause loss of MHC-I are rarely found5 despite the frequent downregulation of MHC-I expression6-8. Here we show that, in PDAC, MHC-I molecules are selectively targeted for lysosomal degradation by an autophagy-dependent mechanism that involves the autophagy cargo receptor NBR1. PDAC cells display reduced expression of MHC-I at the cell surface and instead demonstrate predominant localization within autophagosomes and lysosomes. Notably, inhibition of autophagy restores surface levels of MHC-I and leads to improved antigen presentation, enhanced anti-tumour T cell responses and reduced tumour growth in syngeneic host mice. Accordingly, the anti-tumour effects of autophagy inhibition are reversed by depleting CD8+ T cells or reducing surface expression of MHC-I. Inhibition of autophagy, either genetically or pharmacologically with chloroquine, synergizes with dual ICB therapy (anti-PD1 and anti-CTLA4 antibodies), and leads to an enhanced anti-tumour immune response. Our findings demonstrate a role for enhanced autophagy or lysosome function in immune evasion by selective targeting of MHC-I molecules for degradation, and provide a rationale for the combination of autophagy inhibition and dual ICB therapy as a therapeutic strategy against PDAC.


Assuntos
Adenocarcinoma/imunologia , Autofagia/imunologia , Carcinoma Ductal Pancreático/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Neoplasias Pancreáticas/imunologia , Evasão Tumoral/imunologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/patologia , Animais , Apresentação do Antígeno/efeitos dos fármacos , Apresentação do Antígeno/imunologia , Autofagia/efeitos dos fármacos , Autofagia/genética , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/imunologia , Linhagem Celular Tumoral , Cloroquina/farmacologia , Feminino , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Masculino , Camundongos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Evasão Tumoral/efeitos dos fármacos
9.
Cancer Immunol Immunother ; 69(9): 1767-1779, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32342128

RESUMO

Targeted immunotherapy has improved the outcome of patients with high-risk neuroblastoma (NB). However, immune escape of tumor cells still occurs and about 40% of NB patients relapse and die from their disease. We previously showed that natural killer (NK) cell stimulation by Toll-like receptor (TLR)-activated plasmacytoid dendritic cells (pDC) increases the efficacy of dinutuximab-based immunotherapy against NB cell lines via the TRAIL death-receptor pathway. With the aim to translate our findings into a novel adoptive therapy of TLR-activated pDC, we investigated the pDC/NK cell axis in NB patients undergoing dinutuximab-based immunotherapy. We show that pDC counts were low at the beginning of immunotherapy but reached normal levels over time. Blood NK cell counts were normal in all patients, although a high proportion of CD56bright CD16low/- cells was observed. The stimulation of patient's blood cells with a TLR9 ligand led to IFN-α production by pDC, and TRAIL expression on NK cell surface. Patient's NK cells expressed high levels of CD69 and TRAIL after stimulation with activated pDC. Both CD56bright CD16low/- and CD56dim CD16+ NK cells degranulated against autologous target cells in the presence of dinutuximab. Importantly, pDC-induced NK cell activation increased the dinutuximab mediated autologous killing of patient-derived NB cells. Altogether, our study demonstrates that TLR-activated pDC strongly increase the cytotoxic functions of NK cells in high-risk NB patients undergoing immunotherapy. These results, therefore, support pDC adoptive immunotherapy as a novel approach to decrease the risk of relapse in patients with high-risk NB.


Assuntos
Anticorpos Monoclonais/farmacologia , Células Dendríticas/imunologia , Células Matadoras Naturais/imunologia , Neuroblastoma/tratamento farmacológico , Neuroblastoma/imunologia , Adolescente , Anticorpos Monoclonais/imunologia , Apresentação do Antígeno/imunologia , Criança , Pré-Escolar , Citotoxicidade Imunológica/imunologia , Feminino , Humanos , Imunoterapia/métodos , Imunoterapia Adotiva/métodos , Ativação Linfocitária/imunologia , Masculino , Recidiva Local de Neoplasia/imunologia , Receptores Toll-Like/imunologia
10.
Nat Commun ; 11(1): 1794, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32286285

RESUMO

Although group 3 innate lymphoid cells (ILC3s) are efficient inducers of T cell responses in the spleen, they fail to induce CD4+ T cell proliferation in the gut. The signals regulating ILC3-T cell responses remain unknown. Here, we show that transcripts associated with MHC II antigen presentation are down-modulated in intestinal natural cytotoxicity receptor (NCR)- ILC3s. Further data implicate microbiota-induced IL-23 as a crucial signal for reversible silencing of MHC II in ILC3s, thereby reducing the capacity of ILC3s to present antigen to T cells in the intestinal mucosa. Moreover, IL-23-mediated MHC II suppression is dependent on mTORC1 and STAT3 phosphorylation in NCR- ILC3s. By contrast, splenic interferon-γ induces MHC II expression and CD4+ T cell stimulation by NCR- ILC3s. Our results thus identify biological circuits for tissue-specific regulation of ILC3-dependent T cell responses. These pathways may have implications for inducing or silencing T cell responses in human diseases.


Assuntos
Apresentação do Antígeno/imunologia , Imunidade Inata , Linfócitos/imunologia , Microbiota , Baço/citologia , Animais , Células Apresentadoras de Antígenos/citologia , Células Apresentadoras de Antígenos/imunologia , Antígenos CD/metabolismo , Polaridade Celular , Regulação para Baixo , Antígenos de Histocompatibilidade Classe II/metabolismo , Interferon gama/metabolismo , Interleucina-23/metabolismo , Ativação Linfocitária/imunologia , Linfócitos/citologia , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Microbiota/genética , Microbiota/imunologia , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fenótipo , Fosforilação , Análise de Componente Principal , Regiões Promotoras Genéticas/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fator de Transcrição STAT3/metabolismo , Linfócitos T/imunologia , Transativadores/genética , Transativadores/metabolismo , Transcrição Genética
11.
Nat Commun ; 11(1): 1817, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32286311

RESUMO

Dendritic cells (DCs) constitute a specialized population of immune cells that present exogenous antigen (Ag) on major histocompatibility complex (MHC) class I molecules to initiate CD8 + T cell responses against pathogens and tumours. Although cross-presentation depends critically on the trafficking of Ag-containing intracellular vesicular compartments, the molecular machinery that regulates vesicular transport is incompletely understood. Here, we demonstrate that mice lacking Kif5b (the heavy chain of kinesin-1) in their DCs exhibit a major impairment in cross-presentation and thus a poor in vivo anti-tumour response. We find that kinesin-1 critically regulates antigen cross-presentation in DCs, by controlling Ag degradation, the endosomal pH, and MHC-I recycling. Mechanistically, kinesin-1 appears to regulate early endosome maturation by allowing the scission of endosomal tubulations. Our results highlight kinesin-1's role as a molecular checkpoint that modulates the balance between antigen degradation and cross-presentation.


Assuntos
Apresentação do Antígeno/imunologia , Células Dendríticas/metabolismo , Endossomos/metabolismo , Cinesina/metabolismo , Ácidos/metabolismo , Animais , Antígenos/metabolismo , Antígenos CD/metabolismo , Células da Medula Óssea/citologia , Proliferação de Células , Endocitose , Antígenos de Histocompatibilidade Classe I/metabolismo , Cinesina/deficiência , Camundongos Knockout , Camundongos Transgênicos , Microtúbulos/metabolismo , Neoplasias/patologia , Ovalbumina/imunologia , Solubilidade
12.
Mol Immunol ; 120: 101-112, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32113130

RESUMO

Histocompatibility Leukocyte Antigens, or HLAs, are one of the most polymorphic molecules in humans. This high degree of polymorphism endows HLA molecules with the ability to present a vast array of peptides, an essential trait for responding to ever-evolving pathogens. Unlike classical HLA molecules (HLA-Ia), some non-classical HLA-Ib molecules, including HLA-E, are almost monomorphic. Several studies show HLA-E can present self-peptides originating from the leader sequence of other HLA molecules, which signals to our immune system that the cell is healthy. Therefore, it was traditionally thought that the chief role of HLA-E in the body was in immune surveillance. However, there is emerging evidence that HLA-E is also able to present pathogen-derived peptides to the adaptive immune system, namely T cells, in a manner that is similar to classical HLA-Ia molecules. Here we describe the early findings of this less conventional role of HLA-E in the adaptive immune system and its importance for immunity.


Assuntos
Antígenos de Histocompatibilidade Classe I/imunologia , Imunidade Adaptativa , Sequência de Aminoácidos , Apresentação do Antígeno/imunologia , Sítios de Ligação , Infecções por Citomegalovirus/imunologia , Infecções por Vírus Epstein-Barr/imunologia , Infecções por HIV/imunologia , Antígeno HLA-A2/química , Antígeno HLA-A2/genética , Antígeno HLA-A2/imunologia , Antígenos de Histocompatibilidade Classe I/química , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Vigilância Imunológica , Células Matadoras Naturais/imunologia , Modelos Moleculares , Polimorfismo Genético , Conformação Proteica , Infecções por Salmonella/imunologia , Homologia de Sequência de Aminoácidos , Linfócitos T/imunologia , Tuberculose/imunologia
13.
Nat Rev Cancer ; 20(4): 203-217, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32161398

RESUMO

The development of immune checkpoint inhibitors (ICIs) is revolutionizing the way we think about cancer treatment. Even so, for most types of cancer, only a minority of patients currently benefit from ICI therapies. Intrinsic and acquired resistance to ICIs has focused research towards new combination therapy approaches that seek to increase response rates, the depth of remission and the durability of benefit. In this Review, we describe how radiotherapy, through its immunomodulating effects, represents a promising combination partner with ICIs. We describe how recent research on DNA damage response (DDR) inhibitors in combination with radiotherapy may be used to augment this approach. Radiotherapy can kill cancer cells while simultaneously triggering the release of pro-inflammatory mediators and increasing tumour-infiltrating immune cells - phenomena often described colloquially as turning immunologically 'cold' tumours 'hot'. Here, we focus on new developments illustrating the key role of tumour cell-autonomous signalling after radiotherapy. Radiotherapy-induced tumour cell micronuclei activate cytosolic nucleic acid sensor pathways, such as cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING), and propagation of the resulting inflammatory signals remodels the immune contexture of the tumour microenvironment. In parallel, radiation can impact immunosurveillance by modulating neoantigen expression. Finally, we highlight how tumour cell-autonomous mechanisms might be exploited by combining DDR inhibitors, ICIs and radiotherapy.


Assuntos
Neoplasias/etiologia , Neoplasias/patologia , Microambiente Tumoral , Animais , Apresentação do Antígeno/imunologia , Apresentação do Antígeno/efeitos da radiação , Biomarcadores Tumorais , Caspases/metabolismo , Reparo do DNA , Suscetibilidade a Doenças , Exossomos/metabolismo , Humanos , Proteínas de Membrana/metabolismo , Terapia de Alvo Molecular , Neoplasias/radioterapia , Nucleotidiltransferases/metabolismo , Processamento de Proteína Pós-Traducional , Radioterapia/efeitos adversos , Radioterapia/métodos , Transdução de Sinais , Microambiente Tumoral/imunologia , Microambiente Tumoral/efeitos da radiação
14.
Cancer Immunol Immunother ; 69(7): 1217-1227, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32157447

RESUMO

Cyclin A1 is a promising antigen for T cell therapy being selectively expressed in high-grade ovarian cancer (OC) and acute myeloid leukemia (AML) stem cells. For adoptive T cell therapy, a single epitope has to be selected, with high affinity to MHC class I and adequate processing and presentation by malignant cells to trigger full activation of specific T cells. In silico prediction with three algorithms indicated 13 peptides of Cyclin A1 9 to 11 amino acids of length to have high affinity to HLA-A*02:01. Ten of them proved to be affine in an HLA stabilization assay using TAP-deficient T2 cells. Their immunogenicity was assessed by repetitive stimulation of CD8+ T cells from two healthy donors with single-peptide-pulsed dendritic cells or monocytes. Intracellular cytokine staining quantified the enrichment of peptide-specific functional T cells. Seven peptides were immunogenic, three of them against both donors. Specific cell lines were cloned and used in killing assays to demonstrate recognition of endogenous Cyclin A1 in the HLA-A*02:01-positive AML cell line THP-1. Immunopeptidome analysis based on direct isolation of HLA-presented peptides by mass spectrometry of primary AML and OC samples identified four naturally presented epitopes of Cyclin A1. The immunopeptidome of HeLa cells transfected with Cyclin A1 and HLA-A*02:01 revealed six Cyclin A1-derived HLA ligands. Epitope p410-420 showed high affinity to HLA-A*02:01 and immunogenicity in both donors. It proved to be naturally presented on primary AML blast and provoked spontaneous functional response of T cells from treatment naïve OC and, therefore, warrants further development for clinical application.


Assuntos
Apresentação do Antígeno/imunologia , Ciclina A1/imunologia , Epitopos de Linfócito T/imunologia , Antígeno HLA-A2/imunologia , Leucemia Mieloide Aguda/imunologia , Neoplasias Ovarianas/imunologia , Linfócitos T Citotóxicos/imunologia , Feminino , Humanos , Leucemia Mieloide Aguda/patologia , Neoplasias Ovarianas/patologia , Fragmentos de Peptídeos/imunologia , Células Tumorais Cultivadas
15.
Life Sci ; 254: 117580, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32205087

RESUMO

Dendritic cells (DCs) are considered as professional antigen presenting cells (APCs), containing a variety of subsets, that can be resident in organs or migrating among the lymphoid and non-lymphoid organs. In a normal steady condition, DCs concomitantly process and present antigens on major histocompatibility complex (MHC) class I and II. However, they are further activated after exposing to antigens. Recently, several approaches have been exerted to improve antigen presentation potency, to elicit powerful immune responses against tumor cells. In DC-based cancer immunotherapy, DC is obtained from patient and modulated ex vivo in order to entice the immune system toward tumor elimination. Several approaches have been on the evaluation for long-term anti-tumor immune responses by DCs. On the other side, combination of DC vaccines with other cancer therapies, like chemotherapy and monoclonal antibodies could confer efficient cancer therapeutics. In this review article, we first go through the immunobiology of DC, and development of DC vaccines. Then, we concentrate on the DC immunotherapy by highlighting combinational approaches to enhance the efficacy of cancer treatment strategies.


Assuntos
Células Dendríticas/imunologia , Imunoterapia , Neoplasias/terapia , Adjuvantes Imunológicos/uso terapêutico , Apresentação do Antígeno/imunologia , Terapia Combinada , Humanos , Neoplasias/imunologia , Radioterapia , Microambiente Tumoral
16.
J Immunol ; 204(1): 3-11, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31848300

RESUMO

CD13/aminopeptidase N is a widely expressed ectoenzyme with multiple functions. As an enzyme, CD13 regulates activities of numerous cytokines by cleaving their N-terminals and is involved in Ag processing by trimming the peptides bound to MHC class II. Independent of its enzymatic activity, cell membrane CD13 functions by cross-linking-induced signal transduction, regulation of receptor recycling, enhancement of FcγR-mediated phagocytosis, and acting as a receptor for cytokines. Moreover, soluble CD13 has multiple proinflammatory roles mediated by binding to G-protein-coupled receptors. CD13 not only modulates development and activities of immune-related cells, but also regulates functions of inflammatory mediators. Therefore, CD13 is important in the pathogenesis of various inflammatory disorders. Inhibitors of CD13 have shown impressive anti-inflammatory effects, but none of them has yet been used for clinical therapy of human inflammatory diseases. We reevaluate CD13's regulatory role in inflammation and suggest that CD13 could be a potential therapeutic target for inflammatory disorders.


Assuntos
Anti-Inflamatórios/farmacologia , Antígenos CD13/antagonistas & inibidores , Antígenos CD13/metabolismo , Inflamação/tratamento farmacológico , Inflamação/patologia , Apresentação do Antígeno/imunologia , Citocinas/metabolismo , Humanos , Fagocitose/imunologia , Receptores de Citocinas/metabolismo , Transdução de Sinais/imunologia
17.
Eur J Pharm Biopharm ; 147: 76-86, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31887349

RESUMO

Although nanoparticle vaccine is one of the promising therapeutic vaccines against cancers and many chronic infections, induction of strong and long-lasting antigen specific T cell response has still remained many challenges. A major challenge in achieving a robust CD8+ T cell response is the requirement of spatio-temporal orchestration of antigen cross-presentation in dendritic cells with innate stimulation. CD8α+ DCs are specialized for cross presentation and critical for cytotoxic T cell responses, which locate in the deeper paracortex of lymph nodes (LNs) in mice. However, due to size exclusion of compartmentalized network in LNs, nanoparticles with a radius of larger than 5 nm are difficult to access to the CD8α+ DCs. Here, we showed that polyethylene glycol-phosphatidylethanolamine (PEG-PE) micelles had an extensive contact with the resident CD8α+ DCs in LNs and delivered more OVA peptides than their free form to these DCs. Meanwhile, successfully delivering antigens into the CD8α+ DCs resulted in the increased cross presentation of antigens and the enhanced generation of effector CD8+ T cell. Our findings further demonstrated the critical role of CD8α+ DCs in cytotoxic T cell immunity in response to PEG-PE micelle-based vaccine, and also provided a valuable approach to generate T cell-mediated immune response.


Assuntos
Antígenos/imunologia , Ovalbumina/administração & dosagem , Peptídeos/administração & dosagem , Vacinas/administração & dosagem , Animais , Apresentação do Antígeno/imunologia , Antígenos CD8/imunologia , Linfócitos T CD8-Positivos/imunologia , Apresentação Cruzada/imunologia , Células Dendríticas/imunologia , Feminino , Linfonodos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Micelas , Nanopartículas , Ovalbumina/imunologia , Peptídeos/imunologia , Linfócitos T Citotóxicos/imunologia , Vacinas/imunologia
18.
Nat Med ; 25(12): 1916-1927, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31792460

RESUMO

Immune-checkpoint blockade (ICB) has demonstrated efficacy in many tumor types, but predictors of responsiveness to anti-PD1 ICB are incompletely characterized. In this study, we analyzed a clinically annotated cohort of patients with melanoma (n = 144) treated with anti-PD1 ICB, with whole-exome and whole-transcriptome sequencing of pre-treatment tumors. We found that tumor mutational burden as a predictor of response was confounded by melanoma subtype, whereas multiple novel genomic and transcriptomic features predicted selective response, including features associated with MHC-I and MHC-II antigen presentation. Furthermore, previous anti-CTLA4 ICB exposure was associated with different predictors of response compared to tumors that were naive to ICB, suggesting selective immune effects of previous exposure to anti-CTLA4 ICB. Finally, we developed parsimonious models integrating clinical, genomic and transcriptomic features to predict intrinsic resistance to anti-PD1 ICB in individual tumors, with validation in smaller independent cohorts limited by the availability of comprehensive data. Broadly, we present a framework to discover predictive features and build models of ICB therapeutic response.


Assuntos
Antígeno CTLA-4/imunologia , Melanoma/tratamento farmacológico , Melanoma/genética , Receptor de Morte Celular Programada 1/imunologia , Anticorpos Monoclonais Humanizados/administração & dosagem , Apresentação do Antígeno/genética , Apresentação do Antígeno/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Masculino , Melanoma/imunologia , Melanoma/patologia , Mutação/genética , Metástase Neoplásica , Nivolumabe/administração & dosagem , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Transcriptoma/genética , Transcriptoma/imunologia , Sequenciamento Completo do Exoma
19.
Int Rev Cell Mol Biol ; 348: 69-121, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31810556

RESUMO

Dendritic cells are at the center of immune responses. They are defined by their ability to sense the environment, take up and process antigen, migrate to secondary lymphoid organs, where they present antigens to the adaptive immune system. In particular, they present lipids and proteins from pathogens, which they encountered in peripheral tissues, to T cells in order to induce a specific effector immune response. These complex antigens need to be broken down into peptides of a certain length in association with Major Histocompatibility Complex (MHC) molecules. Presentation of MHC/antigen complexes alongside costimulatory molecules and secretion of proinflammatory cytokines will induce an appropriate immune response. This interaction between dendritic cells and T cells takes place at defined locations within secondary lymphoid organs. In this review, we discuss the current knowledge and recent advances on the cellular and molecular mechanisms that underlie antigen processing and the subsequent presentation to T lymphocytes.


Assuntos
Apresentação do Antígeno/imunologia , Animais , Células Dendríticas/imunologia , Humanos , Neoplasias/imunologia , Neoplasias/terapia
20.
Nature ; 576(7787): 465-470, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31827286

RESUMO

Tumour-infiltrating lymphocytes are associated with a survival benefit in several tumour types and with the response to immunotherapy1-8. However, the reason some tumours have high CD8 T cell infiltration while others do not remains unclear. Here we investigate the requirements for maintaining a CD8 T cell response against human cancer. We find that CD8 T cells within tumours consist of distinct populations of terminally differentiated and stem-like cells. On proliferation, stem-like CD8 T cells give rise to more terminally differentiated, effector-molecule-expressing daughter cells. For many T cells to infiltrate the tumour, it is critical that this effector differentiation process occur. In addition, we show that these stem-like T cells reside in dense antigen-presenting-cell niches within the tumour, and that tumours that fail to form these structures are not extensively infiltrated by T cells. Patients with progressive disease lack these immune niches, suggesting that niche breakdown may be a key mechanism of immune escape.


Assuntos
Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular , Linfócitos do Interstício Tumoral/citologia , Linfócitos do Interstício Tumoral/imunologia , Neoplasias/imunologia , Células-Tronco/citologia , Animais , Apresentação do Antígeno/genética , Apresentação do Antígeno/imunologia , Linfócitos T CD8-Positivos/metabolismo , Progressão da Doença , Epigênese Genética , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Humanos , Linfócitos do Interstício Tumoral/metabolismo , Camundongos , Neoplasias/patologia , Nicho de Células-Tronco/imunologia , Transcrição Genética , Evasão Tumoral/genética , Evasão Tumoral/imunologia
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