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1.
Access Microbiol ; 6(5)2024.
Artigo em Inglês | MEDLINE | ID: mdl-38868372

RESUMO

KSHV viral FLICE inhibitory protein (vFLIP) is a potent activator of NF-κB signalling and an inhibitor of apoptosis and autophagy. Inhibition of vFLIP function and NF-κB signalling promotes lytic reactivation. Here we provide evidence for a novel function of vFLIP through inhibition of the deubiquitinating (DUB) activity of the negative regulator, A20. We demonstrate direct interaction of vFLIP with Itch and A20 and provide evidence for subsequent loss of A20 DUB activity. Our results provide further insight into the function of vFLIP in the regulation of NF-κB signalling.

2.
Clin Cancer Res ; 30(8): 1431-1433, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38289325

RESUMO

Systemic administration of homeostatic γ-chain cytokines mediates antitumor responses in some patients treated with adoptive immunotherapy. Yet many patients experience toxic side effects. New work presented herein suggests these limitations can be overcome by membrane-tethering IL15 and IL21 to T-cell products. This finding has major implications in advancing medicine. See related article by Nguyen et al., p. 1555.


Assuntos
Interleucina-15 , Linfócitos T , Humanos , Citocinas , Interleucinas , Imunoterapia Adotiva
3.
Nat Rev Cancer ; 23(3): 173-188, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36456755

RESUMO

Targeted immunotherapy has improved patient survival in head and neck squamous cell carcinoma (HNSCC), but less than 20% of patients produce a durable response to these treatments. Thus, new immunotherapies that consider all key players of the complex HNSCC tumour microenvironment (TME) are necessary to further enhance tumour-specific T cell responses in patients. HNSCC is an ideal tumour type in which to evaluate immune and non-immune cell differences because of two distinct TME aetiologies (human papillomavirus (HPV)-positive and HPV-negative disease), multiple anatomic sites for tumour growth, and clear distinctions between patients with locally advanced disease and those with recurrent and/or metastatic disease. Recent technological and scientific advancements have provided a more complete picture of all cellular constituents within this complex TME and have evaluated the interplay of both immune and non-immune cells within HNSCC. Here, we include a comprehensive analysis of the complete ecosystem of the HNSCC TME, performed utilizing data-rich resources such as The Cancer Genome Atlas, and cutting-edge techniques, such as single-cell RNA sequencing, high-dimensional flow cytometry and spatial multispectral imaging, to generate improved treatment strategies for this diverse disease.


Assuntos
Antineoplásicos Imunológicos , Neoplasias de Cabeça e Pescoço , Imunomodulação , Carcinoma de Células Escamosas de Cabeça e Pescoço , Microambiente Tumoral , Humanos , Neoplasias de Cabeça e Pescoço/etiologia , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/terapia , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/etiologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Microambiente Tumoral/imunologia , Antineoplásicos Imunológicos/imunologia , Antineoplásicos Imunológicos/uso terapêutico
4.
Clin Cancer Res ; 28(7): 1335-1344, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35091445

RESUMO

PURPOSE: Concurrent radiotherapy with cetuximab, an anti-EGFR mAb, is a standard treatment for locally advanced head and neck squamous carcinoma (HNSCC). Cytotoxic T lymphocyte antigen-4-positive (CTLA-4+) regulatory T cells (Treg) dampen cellular immunity and correlate negatively with clinical outcomes. This phase I study added ipilimumab, an anti-CTLA-4 mAb, to cetuximab-radiotherapy. PATIENTS AND METHODS: A (3 + 3) design was used to establish the recommended phase II dose (RP2D) of ipilimumab, added at week 5 for four, every-3-week doses to fixed, standard cetuximab-radiotherapy. Eligible subjects had stage III to IVb, high-risk [human papillomavirus-negative (HPV-)] or intermediate-risk HPV-positive (HPV+)] HNSCC. Dose-limiting toxicity (DLT) was defined as any grade 4 adverse event (AE) except in-field radiation dermatitis or immune-related (ir) AE requiring ≥2 weeks of systemic steroids. Baseline tumor and serial blood specimens were collected for immune correlatives. RESULTS: From July 2013 to May 2016, 18 patients enrolled. Two of 6 in cohort 1 (ipilimumab 3 mg/kg) experienced grade 3 dermatologic DLTs, triggering deescalation of ipilimumab to 1 mg/kg. Dose level -1 was expanded to N = 12 without DLT. irAE included: grade 1, 2, and 3 dermatitis (2, 1, and 3 cases), grade 4 colitis (1), and grade 1 hyperthyroidism (1). Three-year disease-free survival (DFS) and overall survival were 72% [90% confidence interval (CI), 57-92] and 72% (90% CI, 56-92). High expression of coinhibitory receptors PD1/LAG3/CD39 on baseline tumor-infiltrating Treg was associated with worse DFS (HR = 5.6; 95% CI, 0.83-37.8; P = 0.08). CONCLUSIONS: The RP2D for ipilimumab plus standard cetuximab-radiotherapy is 1 mg/kg in weeks 5, 8, 11, and 14. The regimen is tolerable and yields acceptable survival without cytotoxic chemotherapy.


Assuntos
Dermatite , Neoplasias de Cabeça e Pescoço , Infecções por Papillomavirus , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cetuximab/efeitos adversos , Dermatite/tratamento farmacológico , Dermatite/etiologia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Ipilimumab/efeitos adversos , Infecções por Papillomavirus/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/etiologia
5.
Cell Rep Med ; 2(12): 100476, 2021 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-34873589

RESUMO

Despite extensive analyses, there remains an urgent need to delineate immune cell states that contribute to mortality in people critically ill with COVID-19. Here, we present high-dimensional profiling of blood and respiratory samples from people with severe COVID-19 to examine the association between cell-linked molecular features and mortality outcomes. Peripheral transcriptional profiles by single-cell RNA sequencing (RNA-seq)-based deconvolution of immune states are associated with COVID-19 mortality. Further, persistently high levels of an interferon signaling module in monocytes over time lead to subsequent concerted upregulation of inflammatory cytokines. SARS-CoV-2-infected myeloid cells in the lower respiratory tract upregulate CXCL10, leading to a higher risk of death. Our analysis suggests a pivotal role for viral-infected myeloid cells and protracted interferon signaling in severe COVID-19.


Assuntos
COVID-19/imunologia , COVID-19/mortalidade , Pulmão/imunologia , SARS-CoV-2/patogenicidade , Idoso , COVID-19/sangue , COVID-19/virologia , Estado Terminal , Citocinas/sangue , Redes Reguladoras de Genes , Humanos , Inflamação , Pulmão/virologia , Modelos Teóricos , Monócitos/imunologia , Células Mieloides/imunologia , Reprodutibilidade dos Testes , Carga Viral
6.
Nat Commun ; 12(1): 3349, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099645

RESUMO

Current immunotherapy paradigms aim to reinvigorate CD8+ T cells, but the contribution of humoral immunity to antitumor immunity remains understudied. Here, we demonstrate that in head and neck squamous cell carcinoma (HNSCC) caused by human papillomavirus infection (HPV+), patients have transcriptional signatures of germinal center (GC) tumor infiltrating B cells (TIL-Bs) and spatial organization of immune cells consistent with tertiary lymphoid structures (TLS) with GCs, both of which correlate with favorable outcome. GC TIL-Bs in HPV+ HNSCC are characterized by distinct waves of gene expression consistent with dark zone, light zone and a transitional state of GC B cells. Semaphorin 4a expression is enhanced on GC TIL-Bs present in TLS of HPV+ HNSCC and during the differentiation of TIL-Bs. Our study suggests that therapeutics to enhance TIL-B responses in HNSCC should be prioritized in future studies to determine if they can complement current T cell mediated immunotherapies.


Assuntos
Linfócitos B/imunologia , Neoplasias de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Estruturas Linfoides Terciárias/metabolismo , Análise de Variância , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos/imunologia , Expressão Gênica , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/virologia , Humanos , Imunoterapia/métodos , Infecções por Papillomavirus , Semaforinas/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia , Análise de Sobrevida , Linfócitos T
7.
bioRxiv ; 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33594364

RESUMO

Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection presents with varied clinical manifestations1, ranging from mild symptoms to acute respiratory distress syndrome (ARDS) with high mortality2,3. Despite extensive analyses, there remains an urgent need to delineate immune cell states that contribute to mortality in severe COVID-19. We performed high-dimensional cellular and molecular profiling of blood and respiratory samples from critically ill COVID-19 patients to define immune cell genomic states that are predictive of outcome in severe COVID-19 disease. Critically ill patients admitted to the intensive care unit (ICU) manifested increased frequencies of inflammatory monocytes and plasmablasts that were also associated with ARDS not due to COVID-19. Single-cell RNAseq (scRNAseq)-based deconvolution of genomic states of peripheral immune cells revealed distinct gene modules that were associated with COVID-19 outcome. Notably, monocytes exhibited bifurcated genomic states, with expression of a cytokine gene module exemplified by CCL4 (MIP-1ß) associated with survival and an interferon signaling module associated with death. These gene modules were correlated with higher levels of MIP-1ß and CXCL10 levels in plasma, respectively. Monocytes expressing genes reflective of these divergent modules were also detectable in endotracheal aspirates. Machine learning algorithms identified the distinctive monocyte modules as part of a multivariate peripheral immune system state that was predictive of COVID-19 mortality. Follow-up analysis of the monocyte modules on ICU day 5 was consistent with bifurcated states that correlated with distinct inflammatory cytokines. Our data suggests a pivotal role for monocytes and their specific inflammatory genomic states in contributing to mortality in life-threatening COVID-19 disease and may facilitate discovery of new diagnostics and therapeutics.

8.
Int J Mol Sci ; 21(17)2020 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-32867034

RESUMO

While T cell-based cancer immunotherapies have shown great promise, there remains a need to understand how individual metastatic tumor environments impart local T cell dysfunction. At advanced stages, cancers that metastasize to the pleural space can result in a malignant pleural effusion (MPE) that harbors abundant tumor and immune cells, often exceeding 108 leukocytes per liter. Unlike other metastatic sites, MPEs are readily and repeatedly accessible via indwelling catheters, providing an opportunity to study the interface between tumor dynamics and immunity. In the current study, we examined CD8+ T cells within MPEs collected from patients with heterogeneous primary tumors and at various stages in treatment to determine (1) if these cells possess anti-tumor activity following removal from the MPE, (2) factors in the MPE that may contribute to their dysfunction, and (3) the phenotypic changes in T cell populations that occur following ex vivo expansion. Co-cultures of CD8+ T cells with autologous CD45- tumor containing cells demonstrated cytotoxicity (p = 0.030) and IFNγ production (p = 0.003) that inversely correlated with percent of myeloid derived suppressor cells, lactate, and lactate dehydrogenase (LDH) within the MPE. Ex vivo expansion of CD8+ T cells resulted in progressive differentiation marked by distinct populations expressing decreased CD45RA, CCR7, CD127, and increased inhibitory receptors. These findings suggest that MPEs may be a source of tumor-reactive T cells and that the cellular and acellular components suppress optimal function.


Assuntos
Linfócitos T CD8-Positivos/citologia , Técnicas de Cocultura/métodos , Interferon gama/metabolismo , Neoplasias/patologia , Derrame Pleural Maligno/patologia , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Diferenciação Celular , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Subunidade alfa de Receptor de Interleucina-7/metabolismo , L-Lactato Desidrogenase/metabolismo , Ácido Láctico/metabolismo , Antígenos Comuns de Leucócito/metabolismo , Masculino , Pessoa de Meia-Idade , Células Supressoras Mieloides/metabolismo , Células Supressoras Mieloides/patologia , Estadiamento de Neoplasias , Neoplasias/complicações , Neoplasias/imunologia , Derrame Pleural Maligno/etiologia , Derrame Pleural Maligno/imunologia , Receptores CCR7/metabolismo , Células Tumorais Cultivadas
9.
Virology ; 501: 119-126, 2017 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-27912080

RESUMO

Expression of Kaposi's sarcoma herpesvirus vFLIP, a potent activator of NFkB signaling, promotes latency. Inhibition of NFkB signaling promotes lytic reactivation. We previously reported that lytic inducer, RTA, inhibits vFLIP induced NFkB signaling by inducing the degradation of vFLIP via the proteasome. Here we report that the cellular ubiquitin ligase, Itch, is required for RTA induced degradation of vFLIP. Expression of either Itch targeting shRNA or a dominant negative mutant of the ubiquitin ligase both increased the stability of vFLIP in the presence of RTA. Itch potently ubiquitinated vFLIP in vivo and in vitro. We provide evidence for interaction between RTA, vFLIP and Itch and we identified an RTA resistant mutant of vFLIP that is unable to interact with Itch. These observations contribute to our understanding of how RTA counteracts the activities of vFLIP.


Assuntos
Infecções por Herpesviridae/enzimologia , Proteínas Imediatamente Precoces/metabolismo , Proteínas Repressoras/metabolismo , Transativadores/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Proteínas Virais/metabolismo , Infecções por Herpesviridae/genética , Infecções por Herpesviridae/virologia , Herpesvirus Humano 8/enzimologia , Herpesvirus Humano 8/genética , Herpesvirus Humano 8/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Proteínas Imediatamente Precoces/genética , Ligação Proteica , Proteólise , Proteínas Repressoras/genética , Transativadores/genética , Ubiquitina-Proteína Ligases/genética , Proteínas Virais/genética
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